Synthesis and antiviral activity of some 1H-pyrrolo[3,2-b]pyridin-6-yl)acetic acid derivatives

Article abstract of DOI:10.14233/ajchem.2017.20372

Pyrrolopyridine derivatives for the treatment of HIV1-infection were synthesized by 10 step reactions. Methyl 2-(3-bromo-7-(4-chlorophenyl)-1,5-dimethyl-1H-pyrrolo[3,2-b]pyridin-6-yl)-2-(tert-butoxy)acetate converted efficiently into the corresponding 1Hpyrrolo[3,2-b]pyridin-6-yl)acetic acid derivatives by Suzuki coupling reaction. Present procedure provides short reaction times and good to excellent yields for a wide range of compounds, including pyrrolopyridine scaffolds. 7-Halogenated 1H-pyrrolo[3,2,b]pyridine acetic acid derivatives of final products showed good activity inthe HIV-1 IN inhibition test, while the other derivatives showed relatively low activity.

Full text of DOI:10.14233/ajchem.2017.20372

Asian Journal of Chemistry; Vol. 29, No. 6 (2017), 1199-1205
ASIAN JOURNAL OF CHEMISTRY
https://doi.org/10.14233/ajchem.2017.20372
Synthesis and Antiviral Activity of Some 1H-Pyrrolo[3,2-b]pyridin-6-yl)acetic Acid Derivatives
1
2
2
2
1,*
HYUN-AH YOON , HWA-JUNG NAM , UK-IL KIM , KYUNGJIN KIM and BONG JIN KIM
1Department of Medicinal Chemistry in Korea Research Institute of Science and Technology, 141, Gajung-ro,Yuseong-gu, Daejeon-si, 34114,
Republic of Korea
2ST PHARM CO., LTD, 231, Hyeomnyeok-ro, Siheung-si, Gyeonggi-do 15086, Republic of Korea
*Corresponding author: E-mail: bjkim@krict.re.kr
Received: 25 October 2016;
Accepted: 6 March 2017;
Published online: 10 April 2017;
AJC-18326
Pyrrolopyridine derivatives for the treatment of HIV1-infection were synthesized by 10 step reactions. Methyl 2-(3-bromo-7-(4-
chlorophenyl)-1,5-dimethyl-1H-pyrrolo[3,2-b]pyridin-6-yl)-2-(tert-butoxy)acetate converted efficiently into the corresponding 1H-
pyrrolo[3,2-b]pyridin-6-yl)acetic acid derivatives by Suzuki coupling reaction. Present procedure provides short reaction times and good
to excellent yields for a wide range of compounds, including pyrrolopyridine scaffolds. 7-Halogenated 1H-pyrrolo[3,2,b]pyridine acetic
acid derivatives of final products showed good activity inthe HIV-1 IN inhibition test, while the other derivatives showed relatively low
activity.
Keywords: Pyrrolopyridine, Suzuki coupling reaction, HIV-1, Integrase.
gel (Merck, 60A pore size, 230-400 mesh). 1H NMR spectra
were recorded on a Bruker 300 MHz or 500 MHz spectrometer
INTRODUCTION
HIV-1 integrase (IN) is essential for viral replication and
it has become one of the most important therapeutic targets.
Many integrase strand transfer inhibitors with different chemical
(Bruker Corporation Ltd., Germany) using CDCl3 or methanol-
d4 as solvent with TMS as the internal standard. Chemical shift
values are given in ppm. Both EI-MS spectra and high resolu-
scaffolds targeting the strand transfer reaction of HIV-1 IN
tion mass spectra (HR-MS) were recorded on a JEOL JMS-
have been developed [1-3].
The chemistry of pyridines and their derivatives has been
700 double-focusing type mass spectrometer. LC-MS data
were obtained on WatersAcquity UPLC H-Class/SQD2 system
studied for over a century because of their diverse biological
(ESI, 70 ev). Elementary analysis was performed on a Thermo
activities and primarily, fused pyridines continue to attract
considerable attention because of their great practical usefulness.
Scientific FLASH EA-2000 organic elemental analyzer.
Following products were obtained from various reactions:
Compounds containing a fused pyridine ring have significant
biological activity and are of particular interest in cancer and
virus research [4-6]. We report herein the synthesis of some
Ethyl 3-amino-1H-pyrrole-2-carboxylate (1): To a
solution of isoxazole (30 g, 0.43 mol) in anhydrous ethanol
new heterocyclic compounds containing pyridine moiety fused
(120 mL) was added drop-wise sodium ethoxide (21 %, in
with pyrrole. In view of the biological importance of HIV-1
IN, we aimed to synthesize a series of 1H-pyrrolo[3,2-b]pyridine
acetic acid (compound 12).
ethanol) (0.45 mol) at 0-5 °C. After stirring for 30 min, acetic
acid (0.43 mol), diethyl amino malonate hydrochloride (0.30
mol), anhydrous sodium acetate (0.33 mol) were added. After
stirring at room temperature for 18 h, the reaction mixture
was concentrated under reduced pressure. The residue was
EXPERIMENTAL
All the chemicals and reagents used in this study were
of laboratory grade and purchased from Aldrich chemical
company.Analytic thin-layer chromatography was performed
on glass plates coated with silica gel (Silicycle, 60A pore size,
40-64 µm particle size) impregnated with a fluorescent
indicator (254 nm). TLC plates were visualized by ultraviolet
light. Flash column chromatography was performed with silica
diluted with chloroform (1.5 L) and water (500 mL), the organic
layer was dried over Na2SO4, filtered and concentrated under
reduced pressure. The residue was dissolved in anhydrous
ethanol (450 mL), sodium ethoxide (21 %, in ethanol) (0.45
mol) was added drop-wise at 0-5 °C. The reaction mixture
was warmed to room temperature slowly, stirred for 18 h, was
quenched with acetic acid (0.45 mol) and basified with aq.

1200 Yoon et al.
Asian J. Chem.
Na2CO3 pH range for 8. The mixture was extracted with chloro-
form (1 L) and washed water (500 mL), dried over anhydrous
magnesium sulfate, filtered and concentrated under reduced
pressure. The residue was purified by silica gel column chro-
ved in phosphoryl chloride (0.43 mol) and the solution was
stirred for 5 h at 60 °C. The solvent was removed from the
reaction mixture. Water/methylene chloride was added and
the layers were separated. The aqueous phase was extracted
with methylene chloride. The combined organic extracts were
dried over magnesium sulfate and concentrated under reduced
pressure, yielding a residue which was purified by column
chromatography (33.3 % ethyl acetate in hexane) to give
1
matograph (25 % ethyl acetate in hexane). Yield (20 %). H
NMR (500 MHz, CDCl3): δ 8.14 (s, 1H), 6.71 (s, 1H), 5.75 (t,
1H, J = 2.8 Hz), 4.33 (m, 4H, J = 6.9 Hz), 1.37 (t, 3H, J = 7.0
Hz); EI-MS m/z: (M++1) 154;Anal. calcd. (%) for C7H10N2O2:
C, 54.54; H, 6.54; N18.17. Found (%): C, 54.78; H, 6.57; N,
16.88.
1
compound 5. Yield (50 %). H NMR (500 MHz, CDCl3): δ
7.27 (d, 1H, J = 3.2 Hz), 6.61 (d, 1H, J = 3.2 Hz), 4.49 (q, 2H,
J = 7.1 Hz), 4.12 (s, 3H), 2.64 (s, 3H), 1.45 (t, 3H, J = 7.2
Hz); EI-MS m/z: (M++1) 252; Anal. calcd. (%) for
C12H13N2O2Cl: C, 57.04; H, 5.19; N, 11.09. Found (%): C,
56.78; H, 5.18; N, 10.99.
(E)-Ethyl 3-[(4-ethyoxy-4-oxobut-2-en-2-yl)amino]-
1H-pyrrole-2-carboxylate (2): Compound 1 (12.8 g, 0.08
mmol) and (Z)-ethyl-3-ethoxy but-2-enoate (0.10 mol) were
dissolved in toluene (250 mL). Then p-toluene sulfonic acid
monohydrate (2.63 mmol) was added and the reaction mixture
was allowed to reflux with stirring for 18 h. The crude products
were purified by silica gel column chromatography (20 % ethyl
acetate in hexane) to give compound 2.Yield (34 %). 1H NMR
(500 MHz, CDCl3): δ 11.28 (d, 1H, J = 1.1 Hz), 8.64 (d, 1H,
J = 1.1 Hz), 6.81 (t, 1H, J = 3.1 Hz), 6.15 (t, 1H, J = 2.8 Hz),
4.71 (s, 1H), 4.43 (q, 2H, J = 7.0 Hz), 4.20 (q, 2H, J = 7.1
Hz), 2.22 (s, 3H), 1.40 (t, 3H, J = 7.2 Hz), 1.29 (t, 3H, J = 7.0
Hz); EI-MS m/z: (M++1) 266;Anal. calcd. (%) for C13H18N2O4:
C, 58.63; H, 6.81; N, 10.52. Found (%): C, 59.00; H, 6.91; N,
10.43.
(7-Chloro-1,5-dimethyl-1H-pyrrolo[3,2-b]pyridin-6-
yl)methanol (6): To a solution of compound 5 (0.73 g, 2.87
mmol) in anhydrous methylene chloride (9 mL) cooled to -78
°C was added drop-wise 1 M DIBAL-H/toluene (8.61 mmol).
The reaction mixture was allowed to slowly warm to -20 °C
and stirred for 1 h. Water (0.5 mL) and 2 N NaOH solution
(0.5 mL) were slowly added for a minute and then the reaction
mixture was filtered over celite and washed with 50 % ethyl
acetate in methanol. Pure compound 6 was provided by column
chromatography (5 % methanol in methylene chloride).Yield
(90 %). 1H NMR (500 MHz, CD3OD-d4): δ 7.44 (d, 1H, J =
3.1 Hz), 6.50 (d, 1H, J = 3.1 Hz), 4.93 (s, 2H), 4.15 (s, 3H),
2.73 (s, 3H); EI-MS m/z: (M++1) 210; Anal. calcd. (%) for
C10H11N2OCl: C, 57.01; H, 5.26; N, 13.30. Found (%): C,
56.58; H, 5.25; N, 13.15.
(E)-Ethyl 3-[(4-ethoxy-4-oxobut-2-en-2-yl)amino]-1-
methyl-1H-pyrrole-2-carboxylate (3): In sequence, compound
2 (7.04 g, 0.026 mol), methyl iodide (0.029 mol), potassium
hydroxide, pellets (0.06 mol) and tetra-n-butylammonium
bromide (TBAB) (3 mmol) were dissolved in methylene chloride
(160 mL). The reaction mixture was stirred for 18 h at room
temperature. Next 2 N HCl solution was added (pH about 7-
8) and then the resulting mixture was extracted with methylene
chloride. We obtained pure compound 3 by silica gel column
chromatography (20 % ethyl acetate in hexane).Yield (87 %).
1H NMR (500 MHz, CDCl3): δ 11.18 (s, 1H), 6.63 (d, 1H, J =
2.8 Hz), 6.00 (d, 1H, J = 2.9 Hz), 4.68 (s, 1H), 4.43 (q, 2H, J
= 7.0 Hz), 4.18 (q, 2H, J = 7.1 Hz), 3.86 (s, 3H), 2.16 (s, 3H),
1.40 (t, 3H, J = 7.1 Hz), 1.28 (t, 3H, J = 7.1 Hz); EI-MS m/z:
(M++1) 280; Anal. calcd. (%) for C14H20N2O4: C, 59.99; H,
7.19; N, 9.99. Found (%): C, 60.24; H, 7.42; N, 10.01.
Ethyl-1,5-dimethyl-7-oxo-4,7-dihydro-1H-pyrrole-
[3,2-b]pyridine-6-carboxylate (4): To the stirred mixture of
compound 3 (5.5 g, 19.5 mmol) in anhydrous ethanol (115 mL)
was added a solution of sodium ethoxide (21 %, in ethanol)
(2.3 mol). After the reaction mixture was stirred and refluxed
for 18 h, 2N-HCl solution was added (pH about 6). Water (80
mL) and methylene chloride (20 mL) were then added and
the reaction mixture was stirred for an additional 1 h. A white
precipitate formed and was filtered off and recrystallized from
water/methylene chloride to produce compound 4. Yield (75
%). 1H NMR (500 MHz, CD3OD-d4): δ 7.17 (d, 1H, J = 2.8
Hz), 6.18 (d, 1H, J = 2.9 Hz), 4.36 (q, 2H, J = 7.1 Hz), 4.11
(s, 3H), 2.43 (s, 3H), 1.39 (t, 3H, J = 7.2 Hz); EI-MS m/z:
(M++1) 234; Anal. calcd. (%) for C12H14N2O3: C, 61.53; H,
6.02; N, 11.96. Found (%): C, 61.41; H, 6.06; N, 11.81.
Ethyl 7-chloro-1,5-dimethyl-1H-pyrrolo[3,2-b]pyridine-
6-carboxylate (5): Compound 4 (2g, 8.54 mmol) was dissol-
[7-(4-Chlorophenyl)-1,5-dimethyl-1H-pyrrolo[3,2-
b]pyridin-6-yl]methanol (7): Compound 6 (0.347g, 4.65
mmol), 4-chlorophenylboronic acid pinacol ester (6.05 mmol),
tetrakis(triphenylphosphine) palladium(0) (1.40 mmol) and
potassium carbonate (23.25 mmol) were dissolved in DMF.
We performed nitrogen degassing of the reaction mixture and
then stirred for 20 min. The reaction mixture was refluxed
with stirring under nitrogen atmosphere for 18 h. The solution
was then allowed to cool to room temperature, filtered over celite,
washed with ethyl acetate and concentrated under reduced
pressure. Then, DMF solvent was removed by high vacuum
pump. We obtained pure compound 7 by silica gel column
chromatography (only ethyl acetate). Yield (52 %). 1H NMR
(500 MHz, CDCl3): δ 7.49 (d, 2H, J = 7.8 Hz), 7.36 (d, 2H,
J = 7.9 Hz), 7.15 (s, 1H), 6.66 (s, 1H), 4.54 (s, 2H), 3.17 (s,
3H), 2.83 (s, 3H); EI-MS m/z: (M++1) 286; Anal. calcd. (%)
for C16H15N2OCl: C, 67.02; H, 5.27; N, 9.77. Found (%): C,
67.72; H, 5.54; N, 9.02.
7-(4-Chlorophenyl)-1,5-dimethyl-1H-pyrrolo[3,2-
b]pyridine-6-carbaldehyde (8): Compound 7 (0.74 mmol)
and manganese(IV) oxide (29.6 mmol) were dissolved in
methylene chloride (30 mL) and then the reaction mixture was
refluxed, while stirring for 18h under nitrogen atmosphere.
The reaction mixture was filtered over celite, washed with ethyl
acetate and concentrated under reduced pressure. Pure com-
pound 8 as a white sold was provided by silica gel column
chromatography (33.3 % ethyl acetate in hexane). Yield (61
%). 1H NMR (500 MHz, CDCl3): δ 9.98 (s, 1H), 7.51 (m, 3H),
7.38 (m, 3H), 6.73 (d, 1H, J = 1.6 Hz), 3.24 (d, 3H, J = 18.3

Vol. 29, No. 6 (2017)
Synthesis and Antiviral Activity of Some 1H-Pyrrolo[3,2-b]pyridin-6-yl)acetic Acid Derivatives 1201
Hz), 2.67 (d, 3H, J = 8.9 Hz); EI-MS m/z: (M++1) 284; Anal.
calcd. (%) for C16H13N2OCl: C, 67.49; H, 4.60; N, 9.84. Found
(%): C, 69.11; H, 4.73; N, 8.97.
the same temperature and then allowed to warm to room
temperature and treated with sodium sulfite. The mixture was
evaporated under reduced pressure. The crude products were
purified by silica gel column chromatography (50 % ethyl
acetate in hexane). Also the products obtained were found to
be pure by TLC and NMR spectra.
Methyl 2-[7-(4-chlorophenyl)-1,5-dimethyl-1H-pyrrolo-
[3,2-b]pyridin-6-yl]-2-hydroxyacetate (9): To the stirred
mixture (ice bath) of compound 8 (0.34 g, 1.2 mmol) and zinc
iodide (2.4 mmol) in dry methylene chloride (11 mL) was added
drop-wise trimethylsilyl cyanide (4.8 mmol) over a period of
20 min. The reaction mixture was stirred for 1 h (ice bath) and
then for a further 3 h at room temperature. The mixture was
dissolved in methylene chloride (30 mL) and washed with
water. The combined organic layers were washed with brine,
dried over anhydrous magnesium sulfate and concentrated to
obtain a yellow solid crude product (2-(7-(4-chlorophenyl)-
1,5-dimethyl-1H-pyrrolo[3,2-b]pyridine-6-yl)-2-((trimethyl-
silyl)oxy)acetonitrile). To the crude product (0.46 g, 100 %
yield on the assumption) in methanol (6.5 mL) was added
sulfuric acid (1.3 mL). The reaction mixture was refluxed while
stirring for 18 h. The reaction mixture was allowed to cool to
room temperature, concentrated and then a saturated aqueous
solution of sodium carbonate (pH about 7) was added. We
performed extraction with ethyl acetate. The organic layer was
dried over magnesium sulfate, the solvent evaporated under
reduced pressure and the residue purified by chromatography
(50 % ethyl acetate in hexane) to give compound 9.Yield (58 %).
1H NMR (500 MHz, CDCl3): δ 7.67 (m, 5H), 6.56 (d, 1H, J =
5.4 Hz), 5.17 (s, 1H), 3.68 (s, 3H), 3.17 (s, 3H), 2.62 (s, 3H);
EI-MS m/z: (M++1) 344; Anal. calcd. (%) for C18H17N2O3Cl:
C, 62.70; H, 4.97; N, 8.12. Found (%): C, 61.02; H, 4.86; N,
7.60.
Methyl 2-[3-bromo-7-(4-chlorophenyl)-1,5-dimethyl-
1H-pyrrolo[3,2-b]pyridin-6-yl]-2-(tert-butoxy)acetate
1
(11a): Yield (99.9 %). H NMR (500 MHz, CDCl3): δ 7.51
(m, 3H), 7.18 (s, 1H), 5.06 (s, 1H), 3.68 (s, 3H), 3.09 (s, 3H)
2.81 (s, 3H) 1.02 (s, 9H); EI-MS m/z: (M++1) 478;Anal. calcd.
(%) for C22H24N2O3BrCl: C, 55.07; H, 5.04; N, 5.84. Found
(%): C, 56.76; H, 5.34; N, 5.66.
Methyl 2-(tert-butoxy)-2-[3-chloro-7-(4-chlorophenyl)-
1,5-dimethyl-1H-pyrrolo[3,2-b]pyridin-6-yl]acetate (11b):
Yield (71.3 %). 1H NMR (500 MHz, CDCl3): δ 7.51 (m, 3H),
7.31 (d, 1H, J = 8.1 Hz), 7.13 (s, 1H), 5.06 (s, 1H), 3.69 (s,
3H), 3.08 (s, 3H) 2.81 (s, 3H) 1.02 (s, 9H); EI-MS m/z: (M++1)
434; C22H24N2O3Cl2: C, 60.70; H, 5.56; N, 6.43. Found (%):
C, 60.77; H, 5.60; N, 6.41.
Methyl 2-(tert-butoxy)-2-[7-(4-chlorophenyl)-3-iodo-
1,5-dimethyl-1H-pyrrolo[3,2-b]pyridin-6-yl]acetate (11c):
Yield (65.8 %). 1H NMR (500 MHz, CDCl3): δ 7.80 (m, 5H),
5.06 (s, 1H), 3.68 (s, 3H), 3.11 (s, 3H) 2.82 (s, 3H) 1.01 (s,
9H); EI-MS m/z: (M++1) 526; Anal. calcd. (%) for
C22H24N2O3ClI: C, 50.16; H, 4.59; N, 5.32. Found (%): C,
51.24; H, 4.68; N, 5.29.
General procedure for Suzuki coupling of aryl com-
pounds with aryl boronic acids (11d-11j): To the stirred
mixture of compound 11a and aryl boronic acid (Table-1, entry
1-7) in 1,2-dimethoxyethane and water was added sodium
carbonate and Pd(dppf)Cl2-DCM (1,1'-bis(diphenylphos-
phino)ferrocene-palladium(II) dichloride dichloromethane
adduct) under nitrogen atmosphere (at -78 °C).After complete
addition, the reaction mixture was stirred for 5 h (reflux). The
mixture was cooled, filtered over celite and evaporated under
reduced pressure. The residue was purified by chromatography
on silica gel (10 % ethyl acetate in hexane). We obtained
various compounds (11d-11j).
Methyl 2-(tert-butoxy)-2-[7-(4-chlorophenyl)-1,5-
dimethyl-1H-pyrrolo[3,2-b]pyridin-6-yl]acetate (10): To a
solution of compound 9 (1.13 g, 2.92 mmol) in methylene
chloride (33 mL) was added tert-butylacetate (65.2 mL) and
then 70 % perchloric acid (14.6 mmol) in methylene chloride
(1 mL) was added drop-wise for 0.5 h. The reaction mixture
was stirred for 3 h at room temperature, then cooled to 10 °C
and an aqueous solution of 20 % sodium carbonate added.
The phases were separated and the aqueous layer was extracted
with ethyl acetate. The combined organic extracts were washed
with water, dried over magnesium sulfate and concentrated
under reduced pressure. Pure compound 10 was provided by
silica gel column chromatography (50 % ethyl acetate in
Methyl 2-(tert-butoxy)-2-[7-(4-chlorophenyl)-1,5-
dimethyl-3-phenyl-1H-pyrrolo[3,2-b]pyridin-6-yl]acetate
(11d): Yield (99.9 %). 1H NMR (500 MHz, CDCl3): δ 8.17 (d,
2H), 7.42 (m, 8H), 5.09 (s, 1H), 3.69 (s, 3H), 3.15 (s, 3H)
2.85 (s, 3H) 1.04 (s, 9H); HRMS (EI) calcd. (%) for
C28H29N2O3Cl (M++1): 476.1867. Found (%) 476.1866.
Methyl 2-(tert-butoxy)-2-[3-(3-chlorophenyl)-7-(4-
chlorophenyl]-1,5-dimethyl-1H-pyrrolo[3,2-b]pyridin-6-
yl)acetate (11e):Yield (53.3 %). 1H NMR (500 MHz, CDCl3):
δ 8.43 (s, 1H), 7.45 (m, 5H), 7.25 (s, 1H), 6.79 (s, 1H), 5.08
(s, 1H), 3.69 (s, 3H), 3.12 (s, 3H), 2.82 (s, 3H) 1.03 (s, 9H);
HRMS (EI) calcd. (%) for C28H29N2O3Cl2 (M++1): 510.1477.
Found (%) 510.1475.
1
hexane) of the residue. Yield (47 %). H NMR (500 MHz,
CDCl3): δ 7.63 (m, 3H), 7.35 (dd, 1H, J = 9.65 Hz), 7.14 (d,
1H, J = 3.2 Hz), 6.68 (d, 1H, J = 3.2 Hz), 5.06 (s, 1H), 3.69 (s,
3H), 3.10 (s, 3H) 2.76 (s, 3H) 1.02 (s, 9H);); EI-MS m/z:
(M++1) 400; Anal. calcd. (%) for C22H26N2O3Cl: C, 65.91; H,
6.29; N, 6.99. Found (%): C, 65.78; H, 6.39; N, 6.78.
General procedure for synthesis of compounds (11a-
11c): To a solution of compound 10 (41 mg, 0.1 mmol) in dry
tetrahydrofuran (THF) (0.8 mL) cooled to -78 °C was added,
drop-wise over a period of 20 min under nitrogen atmosphere,
a solution of N-bromosuccinimde (NBS) (to give compound
11a), N-chlorosuccimide (NCS) (to give compound 11b), or
N-iodosuccimide (NIS) (to give compound 11c) (0.1 mmol),
as appropriate, dissolved in THF (0.6 mL). After complete
addition, the reaction mixture was stirred for a further 1 h at
Methyl 2-(tert-butoxy)-2-[7-(4-chlorophenyl)-1,5-
dimethyl-3-{3-(trifluoromethyl)phenyl}-1H-pyrrolo[3,2-
b]pyridin-6-yl]acetate (11f): Yield (67.9 %). 1H NMR (300
MHz, CDCl3): δ 7.68 (m, 9H), 5.08 (s, 1H), 3.68 (s, 3H), 3.14
(s, 3H), 2.81 (s, 3H) 1.02 (s, 9H); HRMS (EI) calcd. (%) for
C29H28ClF3N2O3 (M++1): 544.1741. Found (%) 544.1740.

1202 Yoon et al.
Asian J. Chem.
TABLE-1
SUZUKI COUPLING OF ARYL COMPOUNDS WITH ARYL BORONIC ACIDS
Entry
Aryl boronic acid
Phenylboronic acid
Time (h)
Yield (%)
Coupling product (11)
1
2
3
4
5
6
7
5
5
5
5
5
5
5
11d
11e
11f
11g
11h
11i
99.9
53.3
67.9
37.0
47.5
21.5
17.4
3-Chlorophenylboronic acid
3-(Trifluoromethyl)phenylboronic acid
3-Biphenylboronic acid
3-Fluorobiphenylboronic acid
3-Furanylboronic acid
3-Methoxy-phenylboronic acid
11j
Methyl 2-(3-([1,1'-biphenyl]-3-yl)-7-(4-chlorophenyl)-
1,5-dimethyl)-1H-pyrrolo[3,2-b]pyridin-6-yl)-2-(tert-
2-(tert-Butoxy)-2-[7-(4-chlorophenyl)-3-iodo-1,5-
dimethyl-1H-pyrrolo[3,2-b]pyridin-6-yl]acetic acid (12c):
Yield 69.9 (%). 1H NMR (500 MHz, CD3OD-d4): δ 7.54 (m,
5H), 5.11 (s, 1H), 3.17 (s, 3H), 2.78 (s, 3H) 1.02 (s, 9H); HRMS
(EI) calcd. (%) for C21H22N2O3ClI (M++1): 512.0354. Found
(%) 512.0347.
1
butoxy)acetate (11g): Yield (37 %). H NMR (300 MHz,
CDCl3): δ 7.85 (m, 14H), 5.07 (s, 1H), 3.68 (s, 3H), 3.14 (s,
3H), 2.81 (s, 3H) 1.02 (s, 9H); HRMS (EI) calcd. (%) for
C34H33N2O3Cl (M++1): 552.2180. Found (%) 552.2178.
Methyl 2-(tert-butoxy)-2-[7-(4-chlorophenyl)-3-(2-
fluoro-[1,1'-biphenyl]-4-yl)-1,5-dimethyl-1H-pyrrolo[3,2-
b]pyridin-6-yl]acetate (11h): Yield (47.5 %). 1H NMR (300
MHz, CDCl3): δ 7.71 (m, 13H), 5.07 (s, 1H), 3.68 (s, 3H),
3.14 (s, 3H), 2.83 (s, 3H) 1.02 (s, 9H); HRMS (EI) calcd. (%)
for C34H32N2O3ClF (M++1): 570.2085. Found (%) 570.2084.
Methyl 2-(tert-butoxy)-2-[7-(4-chlorophenyl)-3-(furan-
3-yl)-1,5-dimethyl-1H-pyrrolo[3,2-b]pyridin-6-yl]acetate
(11i):Yield (21.5 %). 1H NMR (500 MHz, CDCl3): δ 8.43 (s,
1H), 7.45 (m, 5H), 7.25 (s, 1H), 6.79 (s, 1H), 5.08 (s, 1H),
3.69 (s, 3H), 3.12 (s, 3H), 2.82 (s, 3H) 1.03 (s, 9H); HRMS
(EI) calcd. (%) for C26H27ClN2O4 (M++1): 466.1659. Found
(%) 466.1658.
2-(tert-Butoxy)-2-[7-(4-chlorophenyl)-1,5-dimethyl-3-
phenyl-1H-pyrrolo[3,2-b]pyridin-6-yl]acetic acid (12d):Yield
(83.5 %). 1H NMR (300 MHz, CDCl3): δ 7.49 (m, 10H), 4.99 (s,
1H), 3.09 (s, 3H) 2.68 (s, 3H) 0.91 (s, 9H); HRMS (EI) calcd.
(%) for C27H27N2O3Cl (M++1): 462.1710. Found (%) 462.1709.
2-(tert-Butoxy)-2-[3-(3-chlorophenyl)-7-(4-chlorophenyl)-
1,5-dimethyl-1H-pyrrolo[3,2-b]pyridin-6-yl]acetic acid
1
(12e): Yield (64.8 %). H NMR (300 MHz, CDCl3): δ 7.67
(m, 9H), 5.17 (s, 1H), 3.15 (s, 3H), 2.79 (s, 3H) 1.05 (s, 9H);
HRMS (EI) calcd. (%) for C27H26N2O3Cl2 (M++1): 496.1320.
Found (%) 496.1322.
2-(tert-Butoxy)-2-[7-(4-chlorophenyl)-1,5-dimethyl-3-
{3-(trifluoromethyl)phenyl}-1H-pyrrolo[3,2-b]pyridin-6-
1
yl]acetic acid (12f): Yield (60.5 %). H NMR (300 MHz,
Methyl 2-(tert-butoxy)-2-[7-(4-chlorophenyl)-3-(3-
methoxyphenyl)-1,5-dimethyl-1H-pyrrolo[3,2-b]pyridin-6-
yl]acetate. (11j): Yield (17.4 %). 1H NMR (500 MHz, CDCl3):
δ 7.18 (m, 9H), 5.09 (s, 1H), 3.92 (s, 3H), 3.69 (s, 3H), 2.83
(s, 3H) 1.04 (s, 9H); HRMS (EI) calcd. (%) for C29H31N2O4Cl
(M++1): 506.1972. Found (%) 506.1971.
CDCl3): δ 7.87 (m, 9H), 5.17 (s, 1H), 3.17 (s, 3H), 2.79 (s,
3H) 1.05 (s, 9H); HRMS (EI) calcd. (%) for C28H26N2O3ClF3
(M++1): 530.1584. Found (%) 530.1583.
2-(3-([1,1'-Biphenyl]-3-yl)-7-(4-chlorophenyl)-1,5-
dimethyl)-1H-pyrrolo[3,2-b]pyridin-6-yl)-2-(tert-butoxy)-
1
acetic acid (12g): Yield (96.6 %). H NMR (300 MHz,
General procedure for preparation of compounds (11a-j
to 12a-j): Compound 11 (0.013 mmol) was dissolved in THF
(2 mmol) and then 4 N NaOH in methanol solution (1 mmol)
was added. After complete addition, the reaction mixture was
stirred for 4 h at room temperature and an aqueous solution of
2 N HCl added. The phases were separated and the aqueous
layer was extracted with ethyl acetate. The combined organic
extracts were washed with water, dried magnesium sulfate and
concentrated under reduced pressure. Pure compound 12 was
provided by silica gel column chromatography (5 % methanol in
methylene chloride) of the residue.
methnaol-d4): δ 7.63 (m, 14H), 5.09 (s, 1H), 3.21 (s, 3H), 2.86
(s, 3H) 0.96 (s, 9H); HRMS (EI) calcd. (%) for C33H31N2O3Cl
(M++1): 538.2023. Found (%) 538.1993.
2-(tert-Butoxy)-2-[7-(4-chlorophenyl)-3-(2-fluoro-
[1,1'-biphenyl]-4-yl)-1,5-dimethyl-1H-pyrrolo[3,2-b]-
pyridin-6-yl]acetic acid (12h): Yield (64.9 %). 1H NMR (500
MHz, methnaol-d4): δ 7.72 (m, 13H), 5.13 (s, 1H), 3.21 (s,
3H), 2.82 (s, 3H) 1.04 (s, 9H); HRMS (EI) calcd. (%) for
C33H30N2O3ClF (M++1): 556.1929. Found (%) 556.1931.
2-(tert-Butoxy)-2-[7-(4-chlorophenyl)-3-(furan-3-yl)-
1,5-dimethyl-1H-pyrrolo[3,2-b]pyridin-6-yl]acetic acid
2-[3-Bromo-7-(4-chlorophenyl)-1,5-dimethyl-1H-
pyrrolo[3,2-b]pyridin-6-yl]-2-(tert-butoxy)acetic acid (12a):
Yield 79.9 (%). 1H NMR (500 MHz, CD3OD-d4): δ 7.58 (m,
5H), 5.11 (s, 1H), 3.16 (s, 3H), 2.77 (s, 3H) 1.02 (s, 9H); HRMS
(EI) calcd. (%) for C21H22N2O3BrCl (M++1): 464.0502. Found
(%) 464.0472.
1
(12i): Yield (53.3 %). H NMR (500 MHz, methnaol-d4): δ
8.23 (s, 1H), 7.59 (m, 6H), 6.84 (s, 1H), 5.11 (s, 1H), 3.17 (s,
3H), 2.79 (s, 3H) 1.02 (s, 9H); HRMS (EI) calcd. (%) for
C25H25N2O4Cl (M++1): 452.1503. Found (%) 452.1506.
2-(tert-Butoxy)-2-[7-(4-chlorophenyl)-3-(3-methoxy-
phenyl)-1,5-dimethyl-1H-pyrrolo[3,2-b]pyridin-6-yl]acetic
acid (12j): Yield (75.6 %). 1H NMR (500 MHz, methnaol-d4):
δ 7.61 (m, 5H), 7.32 (t, 1H, J = 15.85 Hz), 6.84 (dd, 1H, J =
10.35 Hz), 5.11 (s, 1H), 3.88 (s, 3H), 3.20 (s, 3H) 2.80 (s, 3H)
1.03 (s, 9H); HRMS (EI) calcd. (%) for C28H29ClN2O4 (M++1):
492.1816. Found (%) 492.1814.
2-(tert-Butoxy)-2-[3-chloro-7-(4-chlorophenyl)-1,5-
dimethyl-1H-pyrrolo[3,2-b]pyridin-6-yl]acetic acid (12b):
Yield 81.8 (%). 1H NMR (500 MHz, CD3OD-d4): δ 7.67 (m,
5H), 5.11 (s, 1H), 3.15 (s, 3H), 2.77 (s, 3H) 1.02 (s, 9H); HRMS
(EI) calcd. (%) for C21H22N2O3Cl2 (M++1): 420.1007. Found
(%) 420.1006.

Vol. 29, No. 6 (2017)
Synthesis and Antiviral Activity of Some 1H-Pyrrolo[3,2-b]pyridin-6-yl)acetic Acid Derivatives 1203
Compound 11 was prepared by two processes as follows:
halides were attached to 10 (Scheme-II) and aromatic moieties
were coupled with 11a via the Suzuki coupling reaction (Scheme-
III). Compound 11a was prepared by NBS (N-bromosuccin-
imide). A similar result was produced using NCS (N-chloro-
succinimide) (to give 11b) and NIS (N-iodosuccinimide) (to
give 11c). For the reaction condition of 11a with aryl boronic
acid, refer to the literature (Table-1) [24,25]. The coupling
reaction of 11a was conducted in a mixture of DMF and water
and gave byproducts. The solvent was changed to DME, but
there was no improvement. We used mild reaction conditions
because the reaction temperature was lower than with DMF.
DME was finally shown to be suitable for the task. Compound
11a was reacted with different arylboronic acids under the
same conditions to afford compounds 11d-j with yields of 17.4
to 99 % (Table-1). The method for coupling with aryl boronic
acid was different from that required for alkylboronic acid.
The target compounds 12a-j were finally obtained by the same
method (Scheme-IV, Table-2).
RESULTS AND DISCUSSION
We synthesized new scaffolds of pyrrolo-pyridine deriva-
tives based on a chemical structure study about HIV-activity
[7-9]. This class of compounds is reported to show activities
of the HIV1 virus [10-18].A multistep synthesis was required
for preparing the pyrrolo-pyridine derivative 10 (Scheme-I).
Ethyl 3-amino-1H-pyrrole-2-carboxylate (1) was prepared as
reported in the literature [19]. Treatment of compound 1 with
(Z)-ethyl-3-ethoxybut-2-enoate and p-toluenesulfonic acid
monohydrate yielded compound 2, which in turn was allowed
to substitute at the N-position of the pyrrole to give compound
3 [20]. It is subjected to cyclization to give compound 4 [21],
which existed as a mixture of keto and enol forms, chlorination
(to give 5) and the DIBAL reduction reaction were performed in
sequence, which resulted in the preparation of compound 6. In
order to prepare compound 7, a chloro-phenyl group was attached
to compound 6 via the Suzuki coupling reaction. We obtained
compound 8 by oxidation and then compound 8 was treated
withTMS-CN and methanol in the presence of acidic conditions
as a one-pot reaction to give compound 9. After completing the
reaction for compound 9, we studied the O-t-butylation of
compound 9 because the mechanism of the O-t-butylation
reaction has several problems. First, compound 9 was not comp-
letely dissolved in tert-butyl acetate. Second, we should slowly
add chloric acid because of the probability of self-assembly
between reagents (side products). We attempted to dilute chloric
acid by using methylene chloride and also the reactant was
dissolved in methylene chloride and tert-butyl acetate.A method
was discovered for the preparation of compound 10 when we
repeated a procedure reported in the literature [22,23].
Cl
Cl
O
O
NBS, NCS or NIS
O
O
N
N
O
O
N
N
R
10
11a-c
R = Br (11a); Cl (11b); I (11c
)
Conditions: 11a: NBS, THF, -78 °C, 1 h, 99 %; 11b: NCS, THF, -78 °C,
1 h, 71 %; 11c: NIS, THF, -78 °C, 1 h, 66 %; NBS = N-borosuccinimide,
NCS = N-chlorosuccimide; NIS = iodosuccimide
Scheme-II: Synthesis of pyrrolo-pyridine derivatives 11a-c
O
O
O
O
O
H
N
H
N
OEt
OEt
N
a
O
b
c
d
N
O
OEt
NH2
O
OEt
N
N
H
OEt
N
H
N
H
OEt
4
3
1
2
e
Cl
Cl
Cl
N
Cl
O
O
h
g
N
N
f
OEt
OH
N
N
OH
H
N
N
N
5
6
7
8
i
Cl
Cl
OH
j
O
O
O
N
N
O
O
N
N
9
10
Conditions: (a) (1) NaOEt, AcOH, diethyl aminomalonate-HCl, NaOAc, EtOH, rt, 18h; (2) NaOEt, EtOH, rt, 18h, 20% (two steps); (b) (Z)-ehtyl-3-ethoxybut-2-enoate,
o
p-TsOH-H2O, toluene, reflux, 18h, 34%; (c) MeI, KOH, TBAB, CH2Cl2, rt, 18h, 87%; (d) NaOEt, EtOH, reflux, 18h, 75%; (e) POCl3, 60 C 5h, 50%; (f) dry CH2Cl2, DIBAL/
,
toluene, -78oC, 1h, 90%; (g) 4-chlorophenylboronic acid pinacol ester, [Pd(PPh3)4], K2CO3, DMF, reflux, 18h, 52%; (h) MnO2, CH2Cl2, reflux, 18h, 61%; (i) (1) dry CH2Cl2,
TMS-CN, ZnI2, 0oC (1h) to rt (3h); (2) H2SO4, MeOH, reflux, 18h, 58% (two steps); (j) t-BuOAc, perchloric acid, CH2Cl2, rt, 3 h, 47 %; NaOEt= sodium ethoxide, p-TsOH
= para-toluenesulfonic acid, DIBAL = diisobutylaluminum hydride, TMSCN = trimethylsilyl cyanide, t-BuOAc = tert - butylacetate.
Scheme-I: Synthesis of new scaffold of pyrrolo-pyridine derivatives (10)

1204 Yoon et al.
Asian J. Chem.
Cl
each to a flat microtiter plate in which a sample of a prepared
compound was placed. The sample was incubated for approxi-
mately 4 to 5 days at 17 °C and the virus suppression effect
was determined using an MTT method. The HIV-1 inhibition
test was performed for compounds 12a-j by the above method
with azidothymidine (AZT) and raltegravir as references. The
results show that compounds 12a-c have moderate activity
against HIV-1 and compounds 12d-j have lower activity
(Table-2).
Cl
O
R-B(OH)2
O
O
N
O
N
O
O
N
N
R
Br
11a
11d-j
Conditions: Pd(dppf)Cl2-DCM, Na2CO3, DMF, H2O, reflux, 5 h
Scheme-III: Synthesis of pyrrolo-pyridine derivatives 11d-j
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Cl
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Vol. 29, No. 6 (2017)
Synthesis and Antiviral Activity of Some 1H-Pyrrolo[3,2-b]pyridin-6-yl)acetic Acid Derivatives 1205
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