Preparation of novel pyrrolo[2,3-b]pyridine derivatives via a new concise synthetic approach

Article abstract of DOI:10.1002/bkcs.10212

The pyrrolo[2,3-b]pyridine core structure, a bioisostere of quinolones, is found in several molecules that possess important biological activity. We describe here a new, concise, three-step synthesis of pyrrolo[2,3-b]pyridines starting from L-alanine. A series of 4,7-dihydro-4-oxo-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid derivatives, which have not been previously reported, were synthesized using this approach.

Full text of DOI:10.1002/bkcs.10212

Article
DOI: 10.1002/bkcs.10212
BULLETIN OF THE
N. Guo et al.
KOREAN CHEMICAL SOCIETY
Preparation of Novel Pyrrolo[2,3-b]pyridine Derivatives via a New
Concise Synthetic Approach
*
Na Guo, Haiyong Jia, Xing You, Du Jiang, Kui Lu, and Peng Yu
Key Laboratory of Industrial Microbiology, Ministry of Education, College of Biotechnology, Tianjin Key
Laboratory of Industry Microbiology, College of Biotechnology, Sino-French Joint Lab of Food
Nutrition/Safety and Medicinal Chemistry, Tianjin University of Science & Technology,
Tianjin 300457, China. *E-mail: yupeng@tust.edu.cn
Received October 22, 2014, Accepted December 5, 2014, Published online March 23, 2015
The pyrrolo[2,3-b]pyridine core structure, a bioisostere of quinolones, is found in several molecules that pos-
sess important biological activity. We describe here a new, concise, three-step synthesis of pyrrolo[2,3-b]pyr-
idines starting from L-alanine. A series of 4,7-dihydro-4-oxo-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid
derivatives, which have not been previously reported, were synthesized using this approach.
Keywords: Pyrrolo[2,3-b]pyridine, Quinolones, Knorr reaction, Diazotization
Introduction
resistance, including quinolones, which requires new quino-
lone analogs continuously to replace the existing drugs.7 More
importantly, excessive use of these drugs can cause problems
due to quinolone resistance. Therefore, the development of
new quinolone analogs is urgent.
Over the past 30 years, the synthesis and modification
of quinolone analogs have focused on the pyridin-4-one of
nalidixic acid and the fused pyridine ring. However, a
few modifications have been carried out on the fused pyrrole
ring, because the synthetic route to pyrrolo[2,3-b]pyridines,
such as 4,7-dihydro-4-oxo-1H-pyrrolo[2,3-b]pyridine-5-
carboxylic acids, is too long and the starting materials are
difficult to obtain. For example, Toja reported the synthesis
of 2-methyl-7-ethyl-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-b]
pyridine-5-carboxylic acid in 1986; the reported synthetic
route has eight steps with an overall yield of about 6%.6
This low synthetic efficiency encouraged us to find a new
Quinolones are a known class of synthetic antimicrobial
drugs that can be divided into several types based on their
chemical structure, including naphthyridinic acids, cinnolinic
acids,pyridopyrimidinicacids,andquinolinicacids.Scheme1
shows some representative drugs with the quinolone core.1–4
In addition to these molecules, some analogs containing a pyr-
idine ring fused with a five-membered ring also exhibit excel-
lent activities, especially antimicrobial activity, such as 4,7-
dihydro-4-oxo-1H-thieno[2,3-b]pyridine-5-carboxylic acids5
(1) and 4,7-dihydro-4-oxo-1H-pyrrolo[2,3-b]pyridine-5-
carboxylic acids6 (2) (Figure 1).
According to the 2010 quinolone anti-infectives market
research report, quinolones represent about 10% of the anti-
infectives drug market, and their market share is still increas-
ing rapidly. However, anti-infective drugs are prone to
OH
F
Cl
F
COOEt
F
COOH
N
COOEt
Cl
NH2
H
Cl
N
ciprofloxacin
EtOOC
COOEt
1
O
e
t
N
O
NH2
ou
N
N
H
5
r
H
H
O
4
N
N
H
H
NH2
O
r
o
u
CN
t
e
2
3
O
N
NH2
N
N
H
H
6
7
Scheme 1. Retrosynthetic analysis of ciprofloxacin and compound 3.
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KOREAN CHEMICAL SOCIETY
O
N
O
O
N
O
O
N
O
F
OH
N
OH
OH
N
N
N
N
HN
F
HN
O
Nalidxic acid
Pipemidic acid
lomefloxacin
O
N
O
O
R3
F
O
O
OH
OH
H
N
OH
R2
R6
S
N
N
O
N
R1
R5'
R4
H
NH
moxifloxacin
2
1
Figure 1. Structures of representative quinolone analogs.
approach for the preparation of these types of compounds.
Here we report a new, concise synthesis approach of 4-oxo-
1H-pyrrolo[2,3-b]pyridine-5-carboxylic ester derivatives,
which can be further evaluated as antimicrobial agents in
the future.
(19.3 g, 74 mmol) were added to ethyl acetoacetate (4.3 g,
37 mmol) dissolved in anhydrous toluene (125 mL), and the
reaction mixture was stirred at room temperature under nitro-
gen for 30 min and then heated under reflux for 8 h. The mix-
ture was cooled to room temperature, poured into a saturated
sodium carbonate solution (800 mL), and the resulting mix-
ture was stirred for about 30 min until tin tetrachloride and
sodium carbonate formed a brownish yellow complex. The
reaction solution was extracted with ethyl acetate (3 × 400
mL), washed with brine, dried over anhydrous magnesium
sulfate, concentrated, andpurifiedbycolumnchromatography
to obtain a pale yellow solid (2.6 g, 30%). 1H NMR (400 MHz,
DMSO-d6), δ (ppm): 2.19 (s, 3H), 2.31 (s, 3H), 2.52 (s, 3H),
3.80 (s, 3H), 6.70 (s, 2H), 11.10 (s, 1H). 13C NMR (100 MHz,
DMSO-d6), δ (ppm): 170.2, 153.4, 150.7, 147.8, 127.7, 105.1,
105.0, 100.7, 51.6, 27.1, 11.1, 11.0. ESI-MS, m/z calcd. for
C12H16N3O2. 234.1, found [M + H]+ 234.1.
Experimental
The solvents for the reactions were distilled over Na, CaH2, or
K2CO3 to remove water. For chromatography, 200–300 mesh
silica gel(Qingdao, China)wasused. 1Hand13CNMRspectra
were recorded with a Brucker ARX 400 spectrometer. Chem-
ical shifts are reported in ppm using tetramethylsilane as an
internal standard. Mass spectra were obtained on a Q-TOF
mass spectrometer (Agilent, Santa Clara, CA, USA).
2-Amino-4,5-dimethyl-1H-pyrrole-3-carbonitrile
(7).
A mixture of Ac2O (16.9 g, 165 mmol), AcOH (2.26 g,
37.6 mmol), Et3N (19.0 g, 188 mmol), and 4-
dimethylaminopyridine (0.10 g, 0.75 mmol) was heated to
50 ꢀC. L-Alanyl acid (6.79 g, 76.2 mmol) was added in small
portions over 4 h, and the resulting red reaction mixture was
stirred for 8 h at 50 ꢀC; then the residual Ac2O, AcOH, and
Et3N were removed under reduced pressure at 100 ꢀC. Water
(40 mL) and malononitrile (4.71 g, 71.3 mmol) were added to
the residue, and the mixture was slowly poured into a 30%
NaOH solution (25 mL) at a temperature below 60 ꢀC. The
reaction solution was cooled to 0 ꢀC, and the precipitated
orange solid was washed with water (45 mL) and dried under
vacuum to give a beige solid product (6.65 g, 66%). 1H NMR
(400 MHz, DMSO-d6), δ (ppm): 1.83 (s, 3H), 1.92 (s, 3H),
5.32 (s, 2H), 9.80 (s, 1H). ESI-MS, m/z calcd. for C7H9N3Na.
158.2, found [M + Na ]+ 158.2.
Methyl
2,3,6-trimethyl-4-oxo-4,7-dihydro-1H-pyrrolo
[2,3-b]pyridine-5-carboxylate (3). H2SO4 (0.8 mL, 98%)
was slowly added to water (12.6 mL) in a 50-mL round-
bottomed flask. After cooling to 0 ꢀC, 4-amino-2,3,6-tri-
methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylate
(0.2 g,
0.86 mmol) was added slowly and stirred for 1 h at room tem-
perature, and then the reaction solution was cooled to 0 ꢀC.
Sodium nitrite (0.12 g, 1.7 mmol) was dissolved in 1 mL of
water and slowly added to the reaction solution and stirred
for 4 h at 0 ꢀC. After the reaction was completed, the pH of
the solution was adjusted to 7 at 0 ꢀC, then the solution was
extracted with ethyl acetate, washed with brine, dried over
anhydrous magnesium sulfate, concentrated, and purified by
the column chromatography to give a white solid (3) (60
1
mg, 30%). H NMR (400 MHz, DMSO-d6), δ (ppm): 2.22
Methyl 4-amino-2,3,6-trimethyl-1H-pyrrolo[2,3-b]pyri-
(s, 3H), 2.27 (s, 3H), 2.63 (s, 3H), 3.91 (s, 3H), 11.31 (s,
1H), 12.07 (s, 1H). 13C NMR (100 MHz, CDCl3), δ (ppm):
172.0, 163.7, 153.8, 148.3, 127.5, 106.8, 106.5, 100.3,
dine-5-carboxylate (6).
2-Amino-4,5-dimethyl-1H-pyr-
role-3-carbonitrile (5 g, 37 mmol) and tin tetrachloride
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KOREAN CHEMICAL SOCIETY
51.0, 26.3, 10.1, 9.1. ESI-MS, m/z calcd. for C12H15N2O3.
using compound 10 instead of 7 and different halogenated
compounds (methyl iodide for 11a, benzyl chloride for 11b,
n-butyl bromide for 11c, and ethyl bromoacetate for 11d) as
starting material.
235.1, found [M + H]+ 235.3.
2-Amino-1,4,5-trimethyl-1H-pyrrole-3-carbonitrile (8).
2-Amino-4,5-dimethyl-1H-pyrrole-3-carbonitrile
(0.2 g,
Compound 11a (55% yield): 1H NMR (400 MHz, CDCl3),
δ (ppm): 2.31 (s, 3H), 2.34 (s, 3H), 2.60 (s, 3H), 3.72 (s, 3H),
3.94 (s, 3H), 3.95 (s, 3H). 13C NMR (100 MHz, CDCl3), δ
(ppm): 169.4, 158.6, 149.9, 149.5, 132.6, 114.3, 111.0,
104.1, 63.0, 52.2, 28.3, 23.1, 10.2, 9.9. ESI-MS, m/z calcd.
for C14H19N2O3. 263.1, found [M + H]+ 263.1. Compound
1.48 mmol) was dissolved in 5 mL of anhydrous DMF, which
was cooled to 0 ꢀC. Sodium hydride (0.12 g, 60%, 2.96 mmol)
was slowly added and the solution was stirred for 1 h. Methyl
iodide (0.28 g, 1.78 mmol) was added, and the reaction solu-
tion was stirred for an additional 2 h at room temperature.
Ethyl acetate (25 mL) and water (125 mL) were added, and
the organic phase was washed with saturated brine (2 × 100
mL), dried over anhydrous magnesium sulfate, concentrated,
and purified by the column chromatography to obtain a pale
1
11b (53% yield): H NMR (400 MHz, CDCl3), δ (ppm):
2.31 (s, 6H), 2.61 (s, 3H), 3.73 (s, 3H), 3.85 (s, 3H), 5.08
(s, 2H), 7.36 (m, 5H). 13C NMR (100 MHz, CDCl3), δ
(ppm): 169.3, 157.3, 149.6, 136.8, 132.9, 128.5 (3C),
128.2, 128.1 (2C), 114.9, 111.5, 104.2, 77.8, 52.3, 28.4,
23.1, 10.4, 10.0. ESI-MS, m/z calcd. for C20H23N2O3.
339.2, found [M + H]+ 339.3. Compound 11c (55% yield):
1H NMR (400 MHz, CDCl3), δ (ppm): 0.96 (t, J = 7.2 Hz,
3H), 1.47 (m, 2H), 1.77 (m, 2H), 2.29 (s, 3H), 2.32 (s, 3H),
2.58 (s, 3H), 3.69 (s, 3H), 3.92 (s, 3H), 4.03 (t, J = 7.2 Hz,
2H). 13C NMR (100 MHz, CDCl3), δ (ppm): 168.6, 156.8,
148.7, 148.4, 131.4, 113.2, 110.2, 103.2, 51.2, 31.2, 28.7,
27.3, 22.0, 18.2, 12.9, 9.3, 8.9. ESI-MS, m/z calcd. for
C17H25N2O3. 305.2, found [M + H]+ 305.1. Compound 11d
1
yellow compound (8) (160 mg, 50%). H NMR (400 MHz,
CDCl3), δ (ppm): 2.00 (s, 3H), 2.03 (s, 3H), 3.28 (s, 3H),
3.74 (brs, 2H). ESI-MS, m/z calcd. for C8H11N3Na. 172.1,
found [M + Na]+ 172.1.
Methyl 4-amino-1,2,3,6-tetramethyl-1H-pyrrolo[2,3-b]
pyridine-5-carboxylate (9). The synthesis of 9 was carried
out using the same procedure as compound 6 except for using
compound 8 instead of 7 as the starting material (40% yield).
1H NMR (400 MHz, CDCl3), δ (ppm): 2.25 (s, 3H), 2.41 (s,
3H), 2.71 (s, 3H), 3.66 (s, 3H), 3.88 (s, 3H), 6.44 (brs, 2H).
13C NMR (100 MHz, CDCl3), δ (ppm): 170.7, 154.8, 151.4,
147.3, 129.1, 104.6, 104.5, 100.6, 51.1, 28.0, 27.6, 11.2,
9.5. ESI-MS, m/z calcd. for C13H18N3O2. 248.1, found [M
+ H]+ 248.1.
1
(55% yield): H NMR (400 MHz, CDCl3), δ (ppm): 1.31 (t,
J = 7.2 Hz, 3H), 2.31 (s, 3H), 2.34 (s, 3H), 2.61 (s, 3H),
3.72 (s, 3H), 3.93 (s, 3H), 4.29 (q, J = 7.2 Hz, 2H), 4.66 (s,
2H). 13C NMR (100 MHz, CDCl3), δ (ppm): 168.9, 168.3,
156.6, 149.8, 133.3, 114.1, 111.0, 104.1, 71.9, 61.6, 61.2,
52.3, 28.4, 23.2, 14.2, 10.2, 10.0. ESI-MS, m/z calcd. for
C17H23N2O5. 335.1, found [M + H]+ 335.1.
Methyl 1,2,3,6-tetramethyl-4-oxo-4,7-dihydro-1H-pyr-
rolo[2,3-b]pyridine-5- carboxylate (10). The synthesis of
10 was carried out using the same procedure as compound 3
except for using compound 9 instead of 6 as starting material
(44% yield). 1H NMR (400 MHz, CDCl3), δ (ppm): 2.27 (s,
3H), 2.38 (s, 3H), 2.78 (s, 3H), 3.68 (s, 3H), 3.96 (s, 3H),
12.54 (s, 1H). 13C NMR (100 MHz, CDCl3), δ (ppm):
173.2, 164.4, 154.5, 149.0, 130.4, 106.8, 106.5, 100.7,
51.9, 28.0, 27.8, 10.3, 9.6. ESI-MS, m/z calcd. for
C13H17N2O3. 249.1, found [M + H]+ 249.1.
Results and Discussion
Initially, we considered the synthesis of ciprofloxacin,8 and
route 1 was similarly designed to synthesize the target com-
pound 3 (Scheme 1) using 4,5-dimethyl-1H-pyrrol-2-amine
(5) as a key intermediate. Unfortunately, we failed to obtain
the desired product owing to the instability of compound 5.
Compounds 11a–11d. The syntheses of 11a–11d were car-
ried out using the same procedure as compound 8 except for
CN
SnCl4
1) Ac2O, AcOH, Et3N, DMAP
2) NaOH
NH2
H2N
COOH
N
H
O
O
NC
CN
O
7
NH2
O
O
O
NaNO2
H2SO4
O
O
N
N
N
N
H
H
H
3
6
Scheme 2. Synthesis of compound 3.
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KOREAN CHEMICAL SOCIETY
CN
CN
NH2
O
SnCl4
NaH DMF
NH2
O
NH2
N
N
O
O
N
H
N
8
7
9
O
O
O
O
O
NaNO2
H2SO4
NaH
O
O
N
N
N
N
R
H
10
11
11c: R=
11d: R=
11a: R= -CH3
11b: R=
O
O
Scheme 3. Synthesis of target compounds 11a–11d.
Consequently, we designed another synthetic route (route 2)
using a Knorr reaction and diazotization as the key steps
(Scheme 1). Compound 7 was synthesized from L-alanine
using a Dakin–West reaction,9–12 and was converted to com-
pound 6 by a Lewis acid-catalyzed Knorr reaction in a sealed
tube under anhydrous conditions.13–17 Compound 6 was
transformed to compound 3 following diazotization and
hydrolysis reactions.18,19 The overall yield of these three steps
was about 10% (Scheme 2).
(81302649), Tianjin Research Program of Application Foun-
dation and Advanced Technology (14JCQNJC13200), and
Scientific Research Program of Tianjin University of Science
and Technology (20120116).
SupportingInformation. Additionalsupportinginformation
is available in the online version of this article.
Several different conditions were investigated for the diazo-
tization and hydrolysis reactions. The best yield was obtained
using 2 equiv. sodium nitrite in H2SO4 at 0 ꢀC for 4 h, fol-
lowed by stirring at room temperature for 2 h. Extending reac-
tion time did not improve the yield, as decomposition of the
product occurred under these conditions.
Target compound 3 contains two NH groups, which facil-
itates further modification of this compound. As both com-
pounds 6 and 3 have poor solubility, they are difficult to
work up and purify. Thus, alkyl groups were introduced onto
the pyrrole and pyridine rings by nucleophilic substitution
with the hope of increasing solubility. The target compounds
11a–11d (Scheme 3) were obtained. Antimicrobial tests of all
the target compounds and key intermediates are going on in
our lab.
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Conclusion
We haveachieved a concise synthesisof methyl 2,3,6-trimethyl-
4-oxo-4,7-dihydro-1H-pyrrolo[2,3-b]pyridine-5-carboxylate
(3). This approach could be further adapted to synthesize more
diverse quinolone analogs by different derivatization at the NH
groups in 3.
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Acknowledgments. This work was financially supported by
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the National Natural Science Foundation of China
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