Efficient and library-friendly synthesis of 4-N-substituted 6-bromopyrido[2,3-d]pyrimidines under microwave irradiation

Article abstract of DOI:10.1007/s11696-018-0498-3

In this paper, a novel synthetic method for 4-N-substituted 6-bromopyrido[2,3-d]pyrimidines was reported. Starting from 2-aminonicotinonitrile, following by bromination of aromatic ring, condensation, cyclization, and Dimroth rearrangement, a series of 21 new pyrido[2,3-d]pyrimidine derivatives was prepared in high yields (up to 98%). In the last two steps, microwave irradiation was used. The structures of synthesized compounds were determined by NMR, IR, and HRMS techniques. The results showed that application of microwave irradiation has a beneficial effect for the preparation of desired products, as it is simple and efficient method for improving the yields and reducing the formation of undesirable by-products.

Full text of DOI:10.1007/s11696-018-0498-3

Chemical Papers
https://doi.org/10.1007/s11696-018-0498-3
ORIGINAL PAPER
Efcient and library‑friendly synthesis of 4‑N‑substituted
6‑bromopyrido[2,3‑d]pyrimidines under microwave irradiation
Ya‑Quan Sun1,2,3 · Chao‑Yang Zong2 · Jin‑Yu Ji1 · Qing Han2
Received: 12 February 2018 / Accepted: 9 May 2018
© Institute of Chemistry, Slovak Academy of Sciences 2018
Abstract
In this paper, a novel synthetic method for 4-N-substituted 6-bromopyrido[2,3-d]pyrimidines was reported. Starting from
2-aminonicotinonitrile, following by bromination of aromatic ring, condensation, cyclization, and Dimroth rearrangement, a
series of 21 new pyrido[2,3-d]pyrimidine derivatives was prepared in high yields (up to 98%). In the last two steps, microwave
irradiation was used. The structures of synthesized compounds were determined by NMR, IR, and HRMS techniques. The
results showed that application of microwave irradiation has a benefcial efect for the preparation of desired products, as it
is simple and efcient method for improving the yields and reducing the formation of undesirable by-products.
Keywords Pyrido[2,3-d]pyrimidines · Dimroth rearrangement · Microwave-assisted synthesis · Organic synthesis
Introduction
particular, they are potent and highly selective inhibitors of
tyrosine kinase (Song et al. 2016; Kammasud et al. 2009),
AK (Zheng et al. 2003) and Cdk4 (Tu et al. 2006). Some of
the biologically active N-substituted fragments at the C-6
position of pyrido[2,3-d]pyrimidine derivatives are shown
in Fig. 1 (Gangjee et al. 2013; Wu et al. 2012; Hou et al.
2016). 4-N-substituted 6-bromopyrido[2,3-d]pyrimidines are
a key intermediates for the synthesis of these compounds, so
methods for their preparation attracted widespread interest.
Traditional preparation of 4-N-substituted
6-bromopyrido[2,3-d]pyrimidines involves the reaction of
amines and 6-bromo-4-chloropyrido[2,3-d]pyrimidine (Hou
et al. 2016). The 6-bromo-4-chloropyrido[2,3-d]pyrimi-
dine was synthesized by chlorination of the corresponding
6-bromopyrido[2,3-d]pyrimidin-4-ol that was in turn pre-
pared by heating 2-amino-5-bromonicotinic acid with formic
acid, triethyl orthoformate, or formamide (Scheme 1). Over-
all, this four-step synthetic route is fairly labor intensive,
requires several intermediate purifcation step, as well as a
relatively high temperature reaction. In our view, access to
the target compounds would require an alternate synthetic
route to be efectively accessed via library synthesis.
The pyrimidine core represents an important group of het-
erocyclic compounds due to its presence in numerous natu-
ral products and structurally diverse synthetic derivatives
(Beyzaei et al. 2017; Mieczkowski et al. 2017). Among com-
pounds containing pyrimidine core, pyridopyrimidines have
received considerable attention over the past years because
of their potential pharmacological activities (Buron et al.
2015; Insuasty et al. 2017; Saurat et al. 2014). Especially,
the pyrido[2,3-d]pyrimidine and its derivatives are useful as
fungicides (Kanth et al. 2006) and as antiviral (Lacbay et al.
2014; Degoey et al. 2013; Krueger et al. 2012), antimicrobial
(Elsaedany et al. 2016; Ravi et al. 2006), and anticancer
(Gineinah et al. 2013; Kurumurthy et al. 2011) agents. In
Electronic supplementary material The online version of this
article (https://doi.org/10.1007/s11696-018-0498-3) contains
supplementary material, which is available to authorized users.
* Ya-Quan Sun
sunyaquan@hotmail.com
Recently, a new methodology for the preparation of
4-aminoquinazolines has been reported in high yields from
reaction of amines and the corresponding N-(2-cyano-
phenyl)-N,N-dimethylformamidine via microwave irra-
diation (Yoon et al. 2004). The procedure is very efcient
and straightforward, providing both ring cyclization and
1
School of Pharmacy, Yancheng Teachers University,
Yancheng 224051, People’s Republic of China
2
Institute of Chemical Technology, Nanjing Tech University,
Nanjing 210000, People’s Republic of China
3
Jiangsu Marine Industry Research Institute,
Yancheng 224051, People’s Republic of China
Vol.:(0123456789)
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Chemical Papers
incorporation of an anilino group at position 4 in a single
step. As the same time, microwave-assisted organic synthe-
sis (MAOS) is also a powerful tool, because it can decrease
reaction times, improves yields and purity of the fnal com-
pounds (Yan et al. 2017; Pan et al. 2017; Hricovíniová et al.
2017). We envisioned that this process could be efectively
to synthesize 4-N-substituted 6-bromopyrido[2,3-d]pyrimi-
dines efectively (Scheme 2).
Experimental
Chemistry
Unless specifed otherwise, all starting materials and rea-
gents were obtained from commercial suppliers without fur-
ther purifcation. All melting points were taken on a MET-
TLEE TOLEDO MP90 melting point apparatus and were
uncorrected. 1H NMR and 13C NMR spectra were recorded
on a Bruker AVANCE III HD 400 MHz instrument using
TMS as the internal standard. Abbreviations used for peak
multiplicities are s: singlet, d: doublet, t: triplet, q: quadru-
plet, and m: multiplet. Coupling constants J are in Hertz and
chemical shifts are given in parts per million and calibrated
Fig. 1 Representative bioactive
C-6 position of pyrido[2,3-d]
pyrimidines
Scheme 1 Traditional preparation of 6-bromo-N-substituted pyrido[2,3-d]pyrimidin-4-amine
Scheme 2 Microwave-assisted synthesis of 4-N-substituted 6-bromopyrido[2,3-d]pyrimidines
1 3

Chemical Papers
with DMSO-d6 or D2O (residual solvent signals). All chemi-
cal shifts were reported in ppm. IR spectra were recorded as
KBr pellets on a VERTEX 80/Raman II FTIR spectrometer.
Mass spectra were recorded on a Triple TOF™ 5600+ (AB
SCIEX USA). The microwave-assisted reactions have been
carried out in a CEM Explorer Hybrid instrument. The reac-
tions were monitored by thin-layer chromatography (TLC)
using silica gel GF254.
Synthesis of (1E)‑N′‑(3‑cyano‑2‑pyridinyl)‑N,N‑dimethylmet
hanimidamide (3)
A suspension of 2-amino-5-bromo-3-pyridinecarbonitrile
(0.59 g, 3 mmol), DMF-DMA (1 ml, 7.5 mmol), and MeCN
(2 ml) was irradiated at 50 °C (input power of: 200 W) for
2 min. The resulting mixture was cooled to room tempera-
ture and poured onto ice cold water. The precipitate was
fltered of, washed with water, and dried to aford (1E)-
N′-(3-cyano-2-pyridinyl)-N,N-dimethylmethanimidamide
(Lacbay et al. 2014). Light yellow solid; yield 95%; m.p.
116–117 °C; 1H NMR (400 MHz, DMSO-d6) δ 8.65–8.60
(m, 1H, H-5), 8.46 (d, J = 2.6 Hz, 1H, H-3), 8.32 (d,
J = 2.6 Hz, 1H, N=CH), 3.16 (s, 3H, CH3), 3.07 (s, 3H,
CH3); 13C NMR (100 MHz, DMSO-d6) δ 162.27 (C-2),
157.00 (C=N), 153.23 (C-6), 144.32 (C-4), 116.77 (CN),
110.23 (C-5), 102.68 (C-3), 35.00 (C–N); IR (flm): 3457
(C–N), 3061, 2916, 2795, 2483, 2306, 2214 (CN), 1960,
1625 (C=N), 1562, 1395 cm−1; HRMS (ESI) m/z: calculated
for C9H10BrN4+ [M+H]+: 253.0089; found: 253.0084.
Synthesis and characterization
Synthesis of 2‑amino‑5‑bromo‑3‑pyridinecarbonitrile (2)
To a solution of 2-aminonicotinonitrile (10 g, 84 mmol)
in dry MeCN (200 ml) NH4Ac (0.64 g, 8.2 mmol) was
added. The reaction was cooled to 0 °C and NBS (16.44 g,
92.4 mmol) was added all at once. After 12 h, solvent was
removed under the reduced pressure and 5% hydrochlo-
ric acid (360 ml) was added until most of product was
redissolved. Resulting solution was filtered, cooled to
0 °C, and basifed to pH > 10 with 6 M NaOH (200 ml).
In 20 min, crystals were collected, washed on the flter
with large amount of water and dried in vacuo afording
2-amino-5-bromo-3-pyridinecarbonitrile (Lacbay et al.
General procedure for the synthesis of 4‑N‑substituted
6‑bromopyrido[2,3‑d]pyrimidine derivatives 5a–u
Conventional heating: (1E)-N′-(3-cyano-2-pyridinyl)-N,N-
dimethylmethanimidamide (3) (0.63 g, 2.5 mmol) and
appropriate amine (2.75 mmol) in acetic acid (5 ml) was
heated to refux for diferent times (140 °C). On completion,
the reaction was cooled to ambient temperature. The result-
ing mixture was evaporated to dryness, the obtained crude
product was fltered, washed with acetic acid, and ether and
1
2014). White crystal; yield 98%; 193–194 °C; H NMR
(400 MHz, DMSO-d6) δ 8.27 (d, J = 2.5 Hz, 1H, H-4),
8.14 (d, J=2.5 Hz, 1H, H-6), 7.13 (s, 2H, NH2); 13C NMR
(100 MHz, DMSO-d6) δ 159.22 (C-2), 154.16 (C-6), 144.01
(C-4), 116.19 (C≡N), 104.28 (C-3), 91.39 (C-5); HRMS
(ESI) m/z: calculated for C6H5BrN3+ [M+H]+: 197.9667;
found: 197.9670.
Table 1 Optimization of the
Entry
Solvent
Amount of DMF-
DMA/equiv
Temperature/°C
Time/min
Yield/%
reaction conditions for the
synthesis of 3
1
2
3
4
5
6
7
8
Toluene
THF
CH3CN
CH3OH
H2O
2.5
2.5
2.5
2.5
2.5
2.5
2
50
50
50
50
50
50
50
50
50
90
70
30
50
50
50
10
10
10
10
10
10
10
10
10
10
10
10
7
89
95
95
87
71
66
90
85
80
95
95
89
95
95
79
–
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
1.5
1
9
10
11
14
15
16
17
2.5
2.5
2.5
2.5
2.5
2.5
4
2
Reaction conditions: 2 (3 mmol), solvent (2 ml) and microwave power 200 W
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Chemical Papers
Table 2 Optimization of the reaction conditions for the synthesis of
to dryness and obtained crude product was fltered, washed
with a small amount of acetic acid and ether, and then dried
to aford the target compound.
5c
Entry
Amount of
Temperature/°C
Time/min
Yield/%
anilines/equiv
1
2
3
4
5
6
7
1
110
110
110
120
100
120
120
6
6
6
6
6
9
3
84
87
92
94
91
94
94
Results and discussion
1.1
1.2
1.2
1.2
1.2
1.2
In our previous work, we reported the synthesis of 4-N-sub-
stituted pyrido[2,3-d]pyrimidines using condensation, cycli-
zation, and then Dimroth rearrangement reaction under
microwave irradiation (Zong et al. 2018). To prepare com-
pounds with better biological activity, we decided to intro-
duce bromine atoms to pyridine ring. Based on our previ-
ous experiences and using similar reaction sequence, a new
series of 4-N-substituted 6-bromopyrido[2,3-d]pyrimidines
was synthesized.
Reaction conditions: 3 (2 mmol), 4c: 4-methoxyaniline, solvent: ace-
tic acid (5 ml), microwave irradiation (200 W)
dried to aford the target compound (Vercek et al. 1979;
Zong et al. 2018).
Our initial eforts focused on the search to fnd opti-
mized conditions for the synthesis of (1E)-N′-(3-cyano-2-
pyridinyl)-N,N-dimethylmethanimidamide (3). After opti-
mization of the microwave conditions by varying solvent,
reaction time, temperature, and amount of DMF-DMA, we
were able to obtain the expected product 3 at 50 °C, 4 min
Microwave irradiation A mixture of (1E)-N′-(3-cyano-
2-pyridinyl)-N,N-dimethylmethanimidamide 3 (0.63 g,
2.5 mmol) and appropriate amine (2.75 mmol) in acetic acid
(5 ml) was irradiated at 120 °C (input power of: 200 W) for
diferent times. On completion, the reaction was cooled to
ambient temperature. The resulting mixture was evaporated
Table 3 Comparison of
conventional and microwave
conditions on the compounds
5a–u
Product
R
Conventional
methoda
Yield/%
Microwave methodb
Yield/%
t/min
t/min
5a
5b
5c
5d
5e
5f
5 g
5 h
5i
Ph
86
88
94
83
85
82
67
77
91
80
93
74
69
83
70
94
71
80
94
89
84
120
180
90
90
90
94
85
88
89
71
82
96
85
98
79
71
88
76
94
72
83
95
92
85
3
6
3
9
3
9
6
6
3
6
3
15
30
15
6
3
3
3
3
3-OMe–C6H4
4-OMe–C6H4
2-Me–C6H4
4-Me–C6H4
2-Cl–C6H4
3-Cl–C6H4
3-Br–C6H4
4-Br–C6H4
3-F–C6H4
240
120
180
180
180
120
150
120
240
240
180
180
120
120
120
120
120
120
5j
5 k
5 l
5 m
5n
5o
5p
5q
5r
4-F–C6H4
4-CN–C6H4
4-NO2–C6H4
3-CH≡C–C6H4
4-C(CH3)3–C6H4
3-Cl–4-F–C6H3
3,5-Me2C6H3
3,5-Cl2C6H3
3,5-F2C6H3
Ph(CH2)2-
5 s
5t
5u
3
3
(CH3)3CH2-
aReaction conditions: 3 (2.5 mmol), amine (3 mmol), solvent: acetic acid (5 ml) and oil bath refux
(130 °C)
bReaction conditions: 3 (2.5 mmol), amine (3 mmol), solvent: acetic acid (5 ml), 120 °C (200 W)
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Chemical Papers
Table 4 Characterization data of synthesized compounds 5a–u
Compound Characterizing data
5a
Yellow solid; m.p. 234–235 °C; IR (flm):3343 (N–H), 3219, 3038, 2930, 1620 (C=N), 1558, 1493, 1389, 1327 (C–N) cm−1
1H NMR (400 MHz, DMSO-d6) δ 10.12 (s, 1H, NH, exchangeable with D2O), 9.35 (d, J=2.4 Hz, 1H, H-7), 9.14 (d, J=2.4 Hz,
1H, H-2), 8.76 (s, 1H, H-5), 7.85 (d, J=7.8 Hz, 2H, Ar–H), 7.43 (t, J=7.9 Hz, 2H, Ar–H), 7.19 (t, J=7.4 Hz, 1H, Ar–H)
13C NMR (100 MHz, DMSO-d6) δ 158.75 (C-8a), 158.61 (C-4), 157.35 (C-2), 157.13 (C-7), 139.04 (C-1′), 135.27 (C-4′), 129.07
(2C, C-3′, C-5′), 124.82 (C-5), 122.83 (2C, C-2′, C-6′), 116.69 (C-6), 111.70 (C-4a)
HRMS, m/z: (M+H)+ calcd for C13H10BrN4 301.0089, found: 301.0084
5b
Golden solid; m.p. 240–241 °C; IR (flm): 3347 (N–H), 3050, 1628 (C=N), 1563, 1498, 1395, 1339 (C–N) cm−1
1H NMR (400 MHz, DMSO-d6) δ 10.06 (s, 1H, NH, exchangeable with D2O), 9.36 (d, J=2.2 Hz, 1H, H-7), 9.15 (d, J=2.2 Hz,
1H, H-2), 8.80 (s, 1H, H-5), 7.63–7.43 (m, 2H, Ar–H), 7.34 (t, J=8.2 Hz, 1H, Ar–H), 6.77 (dd, J=8.2, 2.4 Hz, 1H, Ar–H), 3.80
(s, 3H, OCH3)
13C NMR (100 MHz, DMSO-d6) δ 159.84 (C-3′), 158.61 (C-8a), 158.51 (C-4), 157.29 (C-2), 157.09 (C-7), 140.26 (C-1′), 135.19
(C-5′), 129.79 (C-5), 116.72 (C-6), 114.86 (C-4′), 111.72 (C-6′), 110.04 (C-4a), 108.52 (C-2′), 55.59 (O–Me); HRMS, m/z:
(M+H)+ calcd for C14H12BrN4O 331.0194, found: 331.0195
5c
5d
5e
5f
Golden solid; m.p. 264–266 °C; IR (flm): 3265, 3052, 2833, 1617 (C=N), 1564, 1433, 1335 (C–N) cm−1
1H NMR (400 MHz, DMSO-d6) δ 10.05 (s, 1H, NH, exchangeable with D2O), 9.29 (d, J=1.8 Hz, 1H, H-7), 9.12 (d, J=2.2 Hz,
1H, H-2), 8.70 (s, 1H, H-5), 7.70 (d, J=9.0 Hz, 2H, Ar–H), 7.00 (d, J=9.1 Hz, 2H, Ar–H), 3.79 (s, 3H, OCH3)
13C NMR (100 MHz, DMSO-d6) δ 158.79 (C-8a), 157.37 (2C, C-4, C-4′), 156.96 (C-2), 156.70 (C-7), 135.16 (C-1′), 131.81 (C-5),
124.67 (2C, C-2′, C-6′), 116.48 (C-6), 114.27 (2C, C-3′, C-5′), 111.59 (C-4a), 55.73 (O–Me)
HRMS, m/z: (M+H)+ calcd for C14H12BrN4O 331.0194; found: 331.0188
White solid; m.p. 204–206 °C; IR (flm): 3470 (N–H), 3214, 3066, 3022, 2966, 1596 (C=N), 1558, 1480, 1425, 1360 (C–N) cm−1
1H NMR (400 MHz, DMSO-d6) δ 10.04 (s, 1H, NH, exchangeable with D2O), 9.23 (d, J=2.0 Hz, 1H, H-7), 9.12 (d, J=2.3 Hz,
1H, H-2), 8.56 (s, 1H, H-5), 7.36–7.29 (m, 2H, Ar–H), 7.29–7.19 (m, 2H, Ar–H), 2.18 (s, 3H, CH3)
13C NMR (100 MHz, DMSO-d6) δ 159.96 (C-8a), 158.98 (C-4), 157.39 (C-2), 157.10 (C-7), 136.87 (C-1′), 135.31 (C-3′), 131.04
(C-2′), 127.89 (C-5′), 127.30 (C-5), 126.82 (2C, C-4′, C-6′), 116.44 (C-6), 111.22 (C-4a), 18.38 (Me)
HRMS, m/z: (M+H)+ calcd for C14H12BrN4 315.0245, found: 315.0245
Golden solid; m.p. 253–255 °C; IR (flm): 3321 (N–H), 3213, 3041, 2915, 1620 (C=N), 1559, 1429, 1389, 1330 (C–N) cm−1
1H NMR (400 MHz, DMSO-d6) δ 10.05 (s, 1H, NH, exchangeable with D2O), 9.31 (d, J=2.3 Hz, 1H, H-7), 9.12 (d, J=2.4 Hz,
1H, H-2), 8.72 (s, 1H, H-5), 7.70 (d, J=8.3 Hz, 2H, Ar–H), 7.22 (d, J=8.3 Hz, 2H, Ar–H), 2.31 (s, 3H, CH3)
13C NMR (100 MHz, DMSO-d6) δ 158.73 (C-8a), 158.70 (C-4), 157.36 (C-2), 157.03 (C-7), 136.44 (C-1′), 135.22 (C-4′), 134.00
(C-5), 129.50 (2C, C-3′, C-5′), 122.88 (2C, C-2′, C-6′), 116.59 (C-6), 111.66 (C-4a), 21.04 (Me)
HRMS, m/z: (M+H)+ calcd for C14H12BrN4 315.0245, found: 315.0248
Grey white solid; m.p. 142–143 °C; IR (flm): 3111, 3051, 2977, 1599 (C=N), 1474, 1358 (C–N) cm−1
1H NMR (400 MHz, DMSO-d6) δ 9.22 (d, J=2.4 Hz, 1H, H-7), 9.14 (d, J=2.3 Hz, 1H, H-2), 8.58 (s, 1H, H-5), 7.60 (dd, J=7.9,
1.2 Hz, 1H, Ar–H), 7.56–7.49 (m, 1H, Ar–H), 7.44 (td, J=7.7, 1.3 Hz, 1H, Ar–H), 7.35 (td, J=7.8, 1.5 Hz, 1H, Ar–H)
13C NMR (100 MHz, DMSO-d6) δ 159.36 (C-8a), 158.18 (C-4), 157.15 (C-2), 156.97, 136.75 (C-7), 135.35 (C-1′), 130.90 (C-3′),
130.28 (C-2′), 129.56 (C-5′), 128.39 (C-5), 128.24 (2C, C-4′, C-6′), 116.68 (C-6), 111.67 (C-4a)
HRMS, m/z: (M+H)+ calcd for C13H9BrClN4 334.9699, found: 334.9695
5g
5h
5i
Light yellow solid; m.p. 263–264 °C; IR (flm): 3322 (N–H), 3211, 3126, 3046, 1620 (C=N), 1557, 1476, 1387, 1330 (C–N) cm−1
1H NMR (400 MHz, DMSO-d6) δ 10.13 (s, 1H, NH, exchangeable with D2O), 9.40–9.29 (d, J=1.9 Hz, 1H, H-7), 9.13 (d,
J=2.3 Hz, 1H, H-2), 8.81 (s, 1H, H-5), 8.07 (s, 1H, Ar–H), 7.80 (d, J=8.1 Hz, 1H, Ar–H), 7.43 (t, J=8.1 Hz, 1H, Ar–H),
7.28–7.10 (m, 1H, Ar–H);13C NMR (100 MHz, DMSO-d6) δ 158.49 (C-8a), 158.34 (C-4), 157.31 (C-2), 157.22 (C-7), 140.71
(C-1′), 135.20 (C-3′), 133.30 (C-5′), 130.70 (C-5), 124.21 (C-4′), 121.84 (C-2′), 120.72 (C-6′), 116.93 (C-6), 111.72 (C-4a)
HRMS, m/z: (M+H)+ calcd for C13H9BrClN4 334.9699; found: 334.9700
;
Light yellow solid; m.p. 261–263 °C; IR (flm): 3318 (N–H), 3248, 3184, 3065, 1612 (C=N), 1557, 1473, 1355 (C–N) cm−1
1H NMR (400 MHz, DMSO-d6) δ 10.14 (s, 1H, NH, exchangeable with D2O), 9.31 (s, 1H, H-7), 9.15 (d, J=2.2 Hz, 1H, H-2), 8.83
(s, 1H, H-5), 8.20 (s, 1H, Ar–H), 7.88 (d, J=7.5 Hz, 1H, Ar–H), 7.45–7.29 (m, 2H, Ar–H)
13C NMR (100 MHz, DMSO-d6) δ 158.52 (C-8a), 158.41 (C-4), 157.35 (C-2), 157.26 (C-7), 140.81 (C-1′), 135.24 (C-3′), 131.04
(C-5′), 127.13 (C-5), 124.69 (C-4′), 121.73 (C-2′), 121.16 (C-6′), 116.94 (C-6), 111.72 (C-4a)
HRMS, m/z: (M+H)+ calcd for C13H9Br2N4 378.9194; found: 378.9188
Light yellow solid; m.p. 280–282 °C; IR (flm): 3320 (N–H), 3202, 3039, 1620 (C=N), 1557, 1482, 1387,1329 (C–N) cm−1
1H NMR (400 MHz, DMSO-d6) δ 10.18 (s, 1H, NH, exchangeable with D2O), 9.31 (s, 1H, H-7), 9.15 (d, J=2.3 Hz, 1H, H-2), 8.78
(s, 1H, H-5), 7.85 (d, J=8.8 Hz, 2H, Ar–H), 7.60 (d, J=8.8 Hz, 2H, Ar–H)
13C NMR (100 MHz, DMSO-d6) δ 158.52 (C-8a), 158.40 (C-4), 157.27 (C-2), 135.27 (C-7), 131.93 (C-1′), 131.90 (2C, C-3′, C-5′),
124.49 (2C, C-2′, C-6′), 121.31 (C-5), 116.84 (C-4′), 116.48 (C-6), 111.78 (C-4a)
HRMS, m/z: (M+H)+ calcd for C13H9Br2N4 378.9194, found: 378.9196
1 3

Chemical Papers
Table 4 (continued)
Compound Characterizing data
5j
5k
5l
Light yellow solid; m.p. 255–256 °C; IR (flm): 3321 (N–H), 3223, 3148, 3047, 1622 (C=N), 1559, 1485, 1388, 1329 (C–N) cm−1
1H NMR (400 MHz, DMSO-d6) δ 10.16 (s, 1H, NH, exchangeable with D2O), 9.31 (s, 1H, H-7), 9.14 (s, 1H, H-2), 8.82 (s, 1H,
H-5), 7.92 (d, J=11.7 Hz, 1H, Ar–H), 7.64 (d, J=8.1 Hz, 1H, Ar–H), 7.44 (q, J=7.8 Hz, 1H, Ar–H), 7.10–6.83 (m, 1H, Ar–H)
13C NMR (100 MHz, DMSO-d6) δ 163.60 (C-8a), 158.54 (C-4), 158.38 (C-2), 157.34 (C-7), 157.27 (C-1′), 135.21 (C-3′), 118.05
(C-5′), 116.92 (C-5), 111.70 (C-4′), 111.13 (C-2′), 110.92 (C-6′), 109.36 (C-6), 109.10 (C-4a)
HRMS, m/z: (M+H)+ calcd for C13H9BrFN4 318.9995, found: 318.9995
Golden solid; m.p. 248–250 °C; IR (flm): 3290, 3231, 3055, 1637 (C=N), 1567, 1506, 1435, 1341 (C–N) cm−1
1H NMR (400 MHz, DMSO-d6) δ 10.13 (s, 1H, NH, exchangeable with D2O), 9.28 (d, J=2.4 Hz, 1H, H-7), 9.13 (d, J=2.4 Hz,
1H, H-2), 8.73 (s, 1H, H-5), 7.84 (ddd, J=9.0, 5.2, 2.7 Hz, 2H, Ar–H), 7.34–7.20 (m, 2H, Ar–H)
13C NMR (100 MHz, DMSO-d6) δ 158.75 (C-8a), 158.59 (C-4), 157.32 (C-2), 157.17 (C-7), 135.20 (C-1′), 124.89 (2C, C-3′, C-5′),
124.81 (C-5), 116.69 (2C, C-2′, C-6′), 115.84 (C-4′), 115.62 (C-6), 111.57 (C-4a)
HRMS, m/z: (M+H)+ calcd for C13H9BrFN4 318.9995; found: 318.9996
Light yellow solid; m.p. 314–316 °C; IR (flm): 3514, 3189, 3124, 3055, 2226 (CN), 1664, 1631 (C=N), 1564, 1387, 1332 (C–N)
cm−1
1H NMR (400 MHz, DMSO-d6) δ 10.35 (s, 1H, NH, exchangeable with D2O), 9.36 (s, 1H, H-7), 9.19 (d, J=1.8 Hz, 1H, H-2), 8.89
(s, 1H, H-5), 8.15 (d, J=8.3 Hz, 2H, Ar–H), 7.88 (d, J=8.7 Hz, 2H, Ar–H)
13C NMR (100 MHz, DMSO-d6) δ 157.67 (C-8a), 154.27 (C-4), 150.48 (C-2), 143.65 (C-7), 139.10 (C-1′), 135.37 (2C, C-3′, C-5′),
133.47 (C-5), 130.02 (3C, C-2′, C-6′, CN), 122.07 (C-4′), 119.55 (C-6), 117.19 (C-4a)
HRMS, m/z: (M+H)+ calcd for C14H9BrN5 326.0041, found: 326.0037
5m
5n
Yellow solid; m.p. 282–284 °C; IR (flm): 3620, 3301 (N–H), 3063, 1634 (C=N), 1594, 1535 (NO2), 1430, 1341 (C–N) cm−1
1H NMR (400 MHz, DMSO-d6) δ 10.49 (s, 1H, NH, exchangeable with D2O), 9.39 (s, 1H, H-7), 9.21 (s, 1H, H-2), 8.94 (s, 1H,
H-5), 8.33 (d, J=9.1 Hz, 2H, Ar–H), 8.24 (d, J=7.3 Hz, 2H, Ar–H)
13C NMR (100 MHz, DMSO-d6) δ 157.73 (C-8a), 142.85 (C-4), 135.44 (C-2), 126.86 (C-7), 125.14 (C-1′), 121.58 (2C, C-3′, C-5′),
117.32 (2C, C-2′, C-6′), 112.83 (C-5), 112.10 (C-4′), 99.99 (C-6), 87.85 (C-4a)
HRMS, m/z: (M+H)+ calcd for C13H9BrN5O2 345.9940, found: 345.9943
Light yellow solid; m.p. 248–250 °C; IR (flm): 3282, 3054, 1617 (C=N), 1561, 1473, 1350 (C–N) cm−1
1H NMR (400 MHz, DMSO-d6) δ 10.12 (s, 1H, NH, exchangeable with D2O), 9.32 (d, J=2.2 Hz, 1H, H-7), 9.15 (d, J=2.4 Hz,
1H, H-2), 8.81 (s, 1H, H-5), 8.05 (s, 1H, Ar–H), 7.96–7.81 (m, 1H, Ar–H), 7.44 (t, J=7.9 Hz, 1H, Ar–H), 7.27 (d, J=7.7 Hz, 1H,
Ar–H), 4.23 (s, 1H, –C≡CH)
13C NMR (100 MHz, DMSO-d6) δ 158.63 (C-8a), 158.48 (C-4), 157.28 (C-2), 139.43 (C-7), 139.42 (C-1′), 135.26 (C-5′), 129.58
(C-5), 127.81 (C-3′), 125.38 (C-4′), 123.11 (C-2′), 122.38 (C-6′), 116.85 (C-6), 111.73 (C-4a), 83.77 (C-1″), 81.33 (C-2″)
HRMS, m/z: (M+H)+ calcd for C15H10BrN4 325.0089; found: 325.0087
5o
5p
5q
5r
Light yellow solid; m.p. 300–302 °C; IR (flm): 3282, 3046, 2959, 1614 (C=N), 1560, 1474, 1429, 1357 (C–N) cm−1
1H NMR (400 MHz, DMSO-d6) δ 10.07 (s, 1H, NH, exchangeable with D2O), 9.32 (d, J=2.3 Hz, 1H, H-7), 9.12 (d, J=2.3 Hz,
1H, H-2), 8.72 (s, 1H, H-5), 7.72 (d, J=8.7 Hz, 2H, Ar–H), 7.43 (d, J=8.6 Hz, 2H, Ar–H), 1.30 (s, 9H, t-Bu)
13C NMR (100 MHz, DMSO-d6) δ 158.77 (C-8a), 158.70 (C-4), 157.38 (C-2), 157.06 (C-7), 147.30 (C-4′), 136.37 (C-1′), 135.20
(2C, C-3′, C-5′), 125.72 (C-5), 122.65 (2C, C-2′, C-6′), 116.60 (C-6), 111.64 (C-4a), 34.65 (C-1″), 31.67 (3C, C-2″, C-3″, C-4″)
HRMS, m/z: (M+H)+ calcd for C17H18BrN4 357.0715, found: 357.0713
Light yellow solid; m.p. 253–254 °C; IR (flm): 3065, 2930, 1618 (C=N), 1573, 1501, 1430, 1341 (C–N) cm−1
1H NMR (400 MHz, DMSO-d6) δ 10.18 (s, 1H, NH, exchangeable with D2O), 9.29 (d, J=6.1 Hz, 1H, H-7), 9.22–9.03 (m, 1H,
H-2), 8.82 (d, J=4.5 Hz, 1H, H-5), 8.25–8.15 (m, 1H, Ar–H), 7.89–7.77 (m, 1H, Ar–H), 7.49 (td, J=9.0, 5.4 Hz, 1H, Ar–H)
13C NMR (100 MHz, DMSO-d6) δ 158.52 (C-8a), 158.41 (C-4), 157.38 (C-2), 155.38 (C-4′), 152.96 (C-7), 136.36 (C-1′), 135.19
(C-5), 124.20 (C-3′), 122.96 (C-6′), 119.55 (C-2′), 117.38 (C-5′), 116.91 (C-6), 111.58 (C-4a)
HRMS, m/z: (M+H)+ calcd for C13H8BrClFN4: 352.9605, found: 352.9589
Light yellow solid; m.p. 223–224 °C; IR (flm): 3461 (N–H), 3218, 2916, 1624 (C=N), 1565, 1476, 1352 (C–N) cm−1
1H NMR (400 MHz, DMSO-d6) δ 9.96 (s, 1H, NH, exchangeable with D2O), 9.33 (d, J=2.1 Hz, 1H, H-7), 9.12 (d, J=2.3 Hz, 1H,
H-2), 8.75 (s, 1H, H-5), 7.47 (s, 2H, Ar–H), 6.82 (s, 1H, Ar–H), 2.30 (s, 6H, 2CH3)
13C NMR (100 MHz, DMSO-d6) δ 158.71 (C-8a), 157.34 (C-4), 157.06 (C-2), 138.88 (C-7), 138.07 (C-1′), 135.23 (2C, C-3′, C-5′),
126.40 (C-5), 120.48 (2C, C-2′, C-6′), 116.64 (C-4′), 111.67(C-6), 104.27(C-4a), 21.59 (2C, 2Me)
HRMS, m/z: (M+H)+ calcd for C15H14BrN4 329.0402, found: 329.0394
Light yellow solid; m.p. 288–289 °C; IR (flm): 3304 (N–H), 3062, 1703, 1558, 1441, 1385, 1330 (C–N) cm−1
1H NMR (400 MHz, DMSO-d6) δ 10.19 (s, 1H, NH, exchangeable with D2O), 9.30 (s, 1H, H-7), 9.19 (s, 1H, H-2), 8.91 (s, 1H,
H-5), 8.07 (s, 2H, Ar–H), 7.37 (t, J=1.8 Hz, 1H, Ar–H)
13C NMR (100 MHz, DMSO-d6) δ 158.32 (C-8a), 158.12 (C-4), 157.53 (C-2), 144.08 (C-7), 137.83 (C-1′), 135.18 (2C, C-3′, C-5′),
134.32 (C, C-5), 123.42 (C-4′), 120.14 (2C, C-2′, C-6′), 117.17 (C-6), 111.83 (C-4a)
HRMS, m/z: (M+H)+ calcd for C13H8BrCl2N4 368.9309, found: 368.9306
1 3

Chemical Papers
Table 4 (continued)
Compound Characterizing data
5s
Light yellow solid; m.p. 276–278 °C; IR (flm): 3331 (N–H), 3230, 3051, 1626 (C=N), 1475, 1335 (C–N) cm−1
1H NMR (400 MHz, DMSO-d6) δ 9.30 (s, 1H, H-7), 9.17 (s, 1H, H-2), 8.87 (s, 1H, H-5), 7.72 (d, J=9.2 Hz, 2H, Ar–H), 7.00 (t,
J=9.1 Hz, 1H, Ar–H), 2.42 (s, 1H, NH, exchangeable with D2O)
13C NMR (100 MHz, DMSO-d6) δ 158.38 (C-8a), 158.12 (2C, C-3′, C-5′), 157.44 (C-4), 157.16 (C-2), 153.17 (C-7), 135.24 (C-1′),
117.08 (C-5), 111.95 (C-6), 105.07 (C-4a), 104.78 (2C, C-2′, C-6′), 99.33 (C-4′)
HRMS, m/z: (M+H)+ calcd for C13H8BrF2N4 336.9900, found: 336.9901
5t
White solid; m.p. 233–234 °C; IR (flm): 3247, 3112, 3030, 2987, 1570, 1444, 1386, 1332 (C–N) cm−1
1H NMR (400 MHz, DMSO-d6) δ 9.04 (s, 1H, H-7), 9.01 (s, 1H, H-2), 8.77 (br, 1H, NH, exchangeable with D2O), 8.65 (s, 1H,
H-5), 7.37–7.16 (m, 5H, Ar–H), 3.77 (m, 2H, CH2), 2.97 (t, J=7.2 Hz, 2H, CH2)
13C NMR (100 MHz, DMSO-d6) δ 160.41 (C-8a), 159.21 (C-4), 157.18 (C-2), 156.62 (C-7), 139.71 (C-1′), 134.85 (C-5), 129.16
(2C, C-3′, C-5′), 128.86 (2C, C-2′, C-6′), 126.67 (C-4′), 115.93 (C-5), 111.24 (C-4a), 42.96 (CH2), 34.68 (CH2)
HRMS, m/z: (M+H)+ calcd for C15H14BrN4 329.0402, found: 329.0397
5u
White solid; m.p. 190–191 °C; IR (flm): 3222, 3019, 2958, 1581, 1448, 1377, 1333 (C–N) cm−1
1H NMR (400 MHz, DMSO-d6) δ 9.11–8.94 (m, 2H, H-7, H-2), 8.62 (s, 2H, H-5, NH, exchangeable with D2O), 3.53 (m, 2H, H-1′),
1.62 (m, 2H, H-2′), 1.38 (m, 2H, H-3′), 0.93 (t, J=7.3 Hz, 3H, CH3)
13C NMR (100 MHz, DMSO-d6) δ 160.44 (C-8a), 159.23 (C-4), 157.21 (C-2), 156.52 (C-7), 134.93 (C-5), 115.84 (C-6), 111.24
(C-4a), 41.16 (C-1′), 30.82 (C-2′), 20.16 (C-3′), 14.21 (C-4′)
HRMS, m/z: (M+H)+ calcd for C11H14BrN4 281.0402, found: 281.0399
in acetonitrile as solvent with excellent yield (95% after
purifcation).
irradiation in quantitative yields (94% after purifcation)
(Table 2, entry 7).
To check the efect of the solvent on the reaction, various
solvents were also evaluated (Table 1, entries 1–5). As can
be seen from Table 1: polar protic solvents, such as water,
provided 71% yield of product 3 (Table 1, entry 5), whereas
reaction in aprotic organic solvents including toluene, ace-
tonitrile, and THF aforded to good yields of the product
3 (Table 1, entries 1–3). Then, we proceeded the reaction
under solvent-free conditions, but the yield of product 3 was
66% yield only (Table 1, entry 6).
After the establishment of the optimal reaction condi-
tions, a variety of aromatic and aliphatic amines were tested
for this cyclization and then Dimroth rearrangement with 3.
As is evident from Table 3, the result of the reaction depends
on the nucleophilicity of the aniline and also on its acces-
sibility in connection with the steric hindrance of the sub-
stituents. The presence of large groups on the para-position
of the aromatic amine involved an increase of reaction time
and slightly decrease of the yields (e.g., products 5l, 5m,
5o). The reaction time of the aniline in the meta position
is slightly longer and the yield is not high (e.g., products
5b and 5c, 5h and 5i, 5j and 5k). The greater the halogen
atom electronegativity is, the easier the reaction proceeds
and yield is higher (e.g., products 5g, 5h and 5j, 5i and 5k).
Furthermore, the structures of the synthesized 4-N-substi-
tuted 6-bromopyrido[2,3-d]pyrimidines were confrmed by
IR, 1H and 13C NMR, and HRMS analysis (Table 4).
Furthermore, the infuence of the amount of DMF-DMA
was also investigated. It was observed that the yields of
product 3 decreased when the amount of DMF-DMA was
decreased to 2, 1.5, and 1 equiv., respectively (Table 1,
entry 7–9). Next, we explored the reaction temperature and
the study of temperature suggested that 50 °C was optimal
(Table 1, entries 6, 10, and 11).
Compared with the preparation of pyrido[2,3-d]pyrimi-
din-4-amine derivatives (where the pyridine core does not
contain bromine atom, Zong et al. 2018), we have found that
in the case of 4-N-substituted 6-bromopyrido[2,3-d]pyrimi-
dines, the reaction takes place more easily in acetonitrile.
Similar reaction optimization was explored for the last
step which consists in heating diferent amines with 3 in the
presence of acetic acid under microwave irradiation. The
model reactions were conducted using 3 with 1–1.2 equiv
of nucleophilic anilines substituted by p-methoxy groups.
After various trials to optimize reaction parameters (amount
of aniline, time, and temperature), we were able to obtain
the expected 6-bromo-N-(4-methoxyphenyl)pyrido[2,3-
d]pyrimidin-4-amine at 200 W, 120 °C in only 3 min of
Conclusions
In summary, we describe a very useful, rapid and library-
friendly method for the synthesis of 4-N-substituted
6-bromopyrido[2,3-d]pyrimidines via microwave-assisted
condensation of the starting amines with imines obtained by
reaction of 2-amino-5-bromonicotinonitrile with dimethyl-
formamide dimethylacetal. The presented method is simple,
efcient and ofers high yields of desired products in short
reaction times.
1 3

Chemical Papers
alkyltriazole tagged pyrido[2,3-d]pyrimidine derivatives and their
anticancer activity. Eur J Med Chem 46:3462–3468. https://doi.
org/10.1016/j.ejmech.2011.05.011
Acknowledgements Project supported by the Jiangsu Prospective Joint
Research Project (No. BY2016066-02) and College Students Innova-
tion Project (No. 201410324014Z).
Lacbay CM, Mancuso J, Lin YS, Bennett N, Götte M, Tsantrizos YS
(2014) Modular assembly of purine-like bisphosphonates as inhib-
itors of HIV-1 reverse transcriptase. J Med Chem 57:7435–7449.
https://doi.org/10.1021/jm501010f
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