An Efficient Copper-catalyzed Nucleophilic Addition to N-Acyliminium Ions Derived from N-Benzyloxycarbonylamino Sulfones: A Novel Approach to C-3 Functionalization of 2-Phenylimidazo[1,2-a]pyridine

Article abstract of DOI:10.1002/bkcs.11228

A general and efficient method for C-3 functionalization of 2-phenylimidazo[1,2-a]pyridine has been developed. The reaction employs Cu(OTf)₂ as a catalyst at 10 mol% loading, proceeds in dimethyl sulfoxide solvent, and utilizes bench-stable sol

Full text of DOI:10.1002/bkcs.11228

Article
DOI: 10.1002/bkcs.11228
BULLETIN OF THE
H. J. Park and J.-G. Jun
KOREAN CHEMICAL SOCIETY
An Efficient Copper-catalyzed Nucleophilic Addition to N-Acyliminium
Ions Derived from N-Benzyloxycarbonylamino Sulfones: A Novel
Approach to C-3 Functionalization of 2-Phenylimidazo[1,2-a]pyridine
*
Hyeong Jin Park and Jong-Gab Jun
Department of Chemistry and Institute of Applied Chemistry, Hallym University, Chuncheon 24252,
Korea. *E-mail: jgjun@hallym.ac.kr
Received April 24, 2017, Accepted July 17, 2017
A general and efficient method for C-3 functionalization of 2-phenylimidazo[1,2-a]pyridine has been
developed. The reaction employs Cu(OTf)2 as a catalyst at 10 mol% loading, proceeds in dimethyl sulfox-
ide solvent, and utilizes bench-stable solid N-benzyloxycarbonylamino sulfones derived from aromatic
and aliphatic aldehydes as N-acyliminium ion precursors. The imidazo[1,2-a]pyridine products are
obtained in moderate to good yields.
Keywords: Imidazo[1,2-a]pyridines, N-Benzyloxycarbonylamino sulfones, N-Acyliminium ions, C C
bond formation, Copper(II) triflate
Introduction
the nitrogen atom are able to exert a marked enhancement
of the reactivity of the imino derivative. In this context, N-
acyliminium ions are widely used as electrophiles for the
intermolecular addition of carbon-centered nucleophiles for
the synthesis of substituted amines that has found wide-
spread use in the rapid assembly of alkaloids and active
pharmaceutical ingredients.14 N-Benzyloxycarbonylamino
sulfones (1), generally referred to as α-amido sulfones, can
be conveniently prepared from aldehydes and are generally
bench-stable solids, which can be stored for prolonged
times.15 It is known that they can be converted into the cor-
responding protected imines (N-acyliminium ions) on treat-
ment with an appropriate Lewis acid (Scheme 1).16 These
imino derivatives contain a positively charged nitrogen atom
and are thus highly suitable for nucleophilic addition. The
resulting N-acyliminium ions have been widely used in
combination with hard metallic reagents, other nonstabilized
carbanions, metal-stabilized enolates, and other nucleophiles
to prepare a large array of amino derivatives.15
Kumar and co-workers reported one-pot three-component
synthesis of 1-amidomethyl-imidazo[1,2-a]pyridines by
condensation of 2-arylimidazo[1,2-a]pyridines, aryl/hetero-
cyclic aldehydes, and acetamide using Yb(OTf )3 (ytter-
bium(III) trifluoromethanesulfonate) as a catalyst.17 Earlier
to this study, Chaubet et al. also reported similar type aza-
Friedel-Crafts reaction on imidazo[1,2-a]pyridine using
TiCl4 or thiamine–HCl as catalyst.18 We were attracted to
this important product synthesis but needed a more conven-
ient strategy with greater substrate scope and better repro-
ducibility to reliably deliver a variety of substrates for an
ongoing project. In continuation of our research efforts
towards the synthesis of bioactive heterocycles using novel
approaches,19 herein, a general and efficient method for C-
3 functionalization of 2-phenylimidazo[1,2-a]pyridine (2)
Imidazopyridine has been recognized as an indispensable
pharmacophore due to its ubiquitous presence in numerous
bioactive natural products and pharmaceuticals.1 In particu-
lar, imidazo[1,2-a]pyridine, a fused bicyclic 5-6-heterocycle
with one ring junction nitrogen atom and one extra nitrogen
atom in the five-membered ring, is widely encountered in a
number of commercial drugs such as alpidem, zolpidem,
saripidem, and necopidem (Figure 1). It also embedded in a
plethora of compounds involved in the drug development
pipeline.2 Functionalized imidazo[1,2-a]pyridines have
been investigated as antibacterial,3 anticancer,4 antiviral,5
antifungal,6 antiulcer,7 anti-inflammatory,8 antihypertensive,9
and β-amyloid detection agents.10 In addition, few derivatives
exhibited enzyme inhibition11 and antituberculosis activity.12
As a result, in the past decades, much attention has been
devoted toward its synthesis and functionalization by distinct
methods.13 However, some of the methods have been pla-
gued by multiple limitations. Hence, a more general and
novel approach for the functionalization of imidazo[1,2-a]
pyridines is in great demand.
Synthesis of nitrogen-containing compounds via easily
accessible imine intermediates is one of the most important
and convenient routes. As we compared with its counter-
part, C O double bond, C N double bond is a less reac-
tive group. In general, imines are unstable and in situ
formation of imines followed by nucleophile addition in
one-pot is more convenient approach. However, in this
process, several Lewis acids would be deactivated or
decomposed due to the presence of amine and that of water
formation in the reaction. We can modify the electrophilic
aptitude of the C N bond through a proper choice of the
nitrogen-linked group. Electron-withdrawing substituents at
Bull. Korean Chem. Soc. 2017
© 2017 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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KOREAN CHEMICAL SOCIETY
General Experimental Procedure for the Preparation of
1. Aldehyde (2.75 mmol) was added to a solution of ben-
zyl carbamate (2.5 mmol) and sodium p-toluenesulfinate
(2.5 mmol) in water (2.5 mL). The pH was adjusted to
approximately 2 with 88% formic acid (ca. 0.5 mL) and
the mixture was heated at 70ꢀC for 1 h. After cooling, the
white solid was filtered and washed sequentially with water
and petroleum ether to give α-amido sulfone 1.
General Experimental Procedure for the Preparation
of 3 using 1 and 2. To a stirred solution of N-
benzyloxycarbonylamino sulfone (1) (0.24 mmol) and 2-
phenylimidazo[1,2-a]pyridine (2) (0.04 g, 0.20 mmol) in
anhydrous dimethyl sulfoxide (DMSO) (2 mL) was added
Cu(OTf )2 (0.01 g, 0.02 mmol) at room temperature. The
reaction mixture was stirred at 100ꢀC for 24 h under nitro-
gen atmosphere. After completion of the reaction, cooled to
room temperature, water (10 mL) was added and extracted
with EtOAc (2 × 20 mL). The combined organic layer was
washed with H2O (2 × 15 mL), brine (15 mL), dried over
anhydrous Na2SO4 and concentrated in vacuo. The crude
was purified by column chromatography (EtOAc/hexane =
1/3:1/2) to afford the pure product (3).
Figure 1. Structures of alpidem, zolpidem, saripidem, and
necopidem.
by copper-catalyzed nucleophilic addition to N-acyliminium
ions derived from 1 is described.
Benzyl (Phenyl(2-phenylimidazo[1,2-a]pyridin-3-yl)methyl)
carbamate (3a). Yield: 66%; Rf = 0.27 (EtOAc/hexane = 1/
1); white solid; mp 187–189ꢀC; 1H NMR (300 MHz,
CDCl3) δ 7.70–7.64 (4H, m), 7.40–7.27 (11H, m),
7.22–7.15 (3H, m), 6.76 (1H, d, J = 7.8 Hz), 6.65 (1H, t,
J = 6.9 Hz), 5.70 (1H, d, J = 7.8 Hz), 5.09 (2H, s); 13C
NMR (75 MHz, CDCl3) δ 155.8, 145.4, 145.2, 137.9,
136.1, 134.2, 129.2, 129.0, 128.7, 128.6, 128.4, 128.2,
128.1, 126.4, 124.8, 124.0, 118.5, 118.2, 112.6, 67.5, 50.5;
HRMS-ESI m/z [M + H]+ calcd for C28H24N3O2:
434.1869, found 434.1861.
Experimental
All chemicals were obtained from local sources and used as
received unless noted otherwise. All solvents were distilled
from proper dehydrating agents under nitrogen atmosphere
prior to use. For chromatography, commercially available
1
solvents were used without further purification. H-NMR
spectra were recorded on a Varian Mercury-300 MHz FT-
NMR (Varian. Inc., Palo Alto, CA, USA) and 75 MHz for
13C, with the chemical shift (δ) reported in parts per million
(ppm) downfield relative to tetramethylsilane (TMS) and
the coupling constants (J) quoted in Hz. CDCl3 was
employed as a solvent and an internal standard. High reso-
lution mass spectra electrospray ionization (HRMS-ESI)
was obtained on an Agilent 6220 TOF LC/MS spectrometer
(Agilent Technologies, Santa Clara, CA, USA) spectrome-
ter. Melting points were recorded on a MEL-TEMP II
(Triad Scientific, Manasquan, NJ, USA) apparatus and were
uncorrected. All reactions were monitored by thin-layer
chromatography (TLC), followed by exposure of the mix-
tures to UV light and/or staining with p-anisaldehyde and
phosphomolybdic acid (PMA) stain to visualize the reac-
tion spots. Column chromatography was performed using
silica gel (60–120 mesh, Merck, Darmstadt, Germany).
Benzyl ((2-Phenylimidazo[1,2-a]pyridin-3-yl)(p-tolyl)methyl)
carbamate (3b). Yield: 33%; Rf = 0.25 (EtOAc/hexane = 1/
1
1); off-white solid; mp 180–182ꢀC; H NMR (300 MHz,
CDCl3)
δ 7.71–7.60 (4H, m), 7.38–7.29 (8H, m),
7.14–7.09 (5H, m), 6.71 (1H, d, J = 8.4 Hz), 6.56 (1H, t,
J = 6.9 Hz), 5.96 (1H, br s), 5.06 (2H, s), 2.32 (3H, s); 13C
NMR (75 MHz, CDCl3) δ 155.8, 145.2, 145.1 137.8,
136.1, 134.8, 134.2, 129.9, 128.9, 128.6, 128.5, 128.3,
128.1, 126.2, 124.7, 124.2, 118.6, 117.9, 112.4, 67.4, 50.5,
21.3; HRMS-ESI m/z [M + Na]+ calcd for C29H25N3O2Na:
470.1844, found 470.1855.
Benzyl ((4-Methoxyphenyl)(2-phenylimidazo[1,2-a]pyridin-3-
yl)methyl)carbamate (3c). Yield: 35%; Rf = 0.31 (EtOAc/
Scheme 1. N-Benzyloxycarbonylamino sulfones (1) as precursors to N-acyliminium ions in nucleophilic addition.
Bull. Korean Chem. Soc. 2017
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C-3 Functionalization of 2-Phenylimidazo[1,2-a]pyridine
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1
hexane = 1/1); off-white solid; mp 190–192ꢀC; H NMR
(300 MHz, CDCl3) δ 7.67 (2H, d, J = 9.0 Hz), 7.64 (2H,
d, J = 9.0 Hz), 7.39–7.30 (8H, m), 7.17 (1H, td, J = 8.7,
1.5 Hz), 7.10 (2H, d, J = 8.7 Hz), 6.82 (2H, d,
J = 8.7 Hz), 6.67 (1H, d, J = 8.4 Hz), 6.63 (1H, t,
J = 8.4 Hz), 5.75 (1H, d, J = 7.8 Hz), 5.05 (2H, s), 3.77
(3H, s); 13C NMR (75 MHz, CDCl3) δ 159.5, 155.8, 145.4,
145.2, 136.3, 134.6, 130.2, 129.1, 128.6, 128.3, 128.2,
127.7, 124.5, 124.1, 118.9, 118.2, 114.8, 112.5, 67.5, 55.6,
50.5; HRMS-ESI m/z [M + Na]+ calcd for C29H25N3O3Na:
486.1794, found 486.1799.
(1H, t, J = 6.9 Hz), 6.26 (1H, br s), 5.16 (2H, s); 13C
NMR (75 MHz, CDCl3) δ 156.1, 147.8, 145.6, 145.4,
136.1, 129.1, 128.7, 128.6, 128.5, 128.4, 128.3, 127.4,
125.2, 124.1, 123.6, 118.4, 117.7, 113.1, 67.9, 50.5;
HRMS-ESI m/z [M + H]+ calcd for C28H23N4O4:
479.1719, found 479.1713.
Benzyl
(Furan-2-yl(2-phenylimidazo[1,2-a]pyridin-3-yl)
methyl)carbamate (3h). Yield: 52%; Rf = 0.28 (EtOAc/
1
hexane = 1/1); red color solid; mp 160–162ꢀC; H NMR
(300 MHz, CDCl3) δ 7.94 (1H, d, J = 6.9 Hz), 7.68 (2H,
d, J = 6.9 Hz), 7.55 (1H, d, J = 9.0 Hz), 7.40–7.25 (9H,
m), 7.09 (1H, t, J = 6.9 Hz), 6.61 (1H, d, J = 6.6 Hz),
6.58 (1H, t, J = 6.6 Hz), 6.36 (1H, br s), 6.25 (1H, t,
J = 3.0 Hz), 6.12 (1H, d, J = 2.4 Hz), 5.01 (2H, s); 13C
NMR (75 MHz, CDCl3) δ 155.6, 150.5, 145.1, 145.0,
142.8, 135.9, 134.0, 129.0, 128.6, 128.5, 128.4, 128.2,
128.1, 128.0, 124.7, 124.4, 117.7, 116.8, 112.4, 110.7,
108.0, 67.3, 46.1; HRMS-ESI m/z [M + H]+ calcd for
C26H22N3O3: 424.1661, found 424.1666.
Benzyl ((4-Bromophenyl)(2-phenylimidazo[1,2-a]pyridin-
3-yl)methyl)carbamate (3d). Yield: 53%; Rf = 0.27
1
(EtOAc/hexane = 1/1); off-white solid; mp 191–193ꢀC; H
NMR (300 MHz, CDCl3) δ 7.66–7.62 (4H, m), 7.41–7.32
(10H, m), 7.18 (1H, td, J = 7.8, 0.9 Hz), 7.05 (2H, d,
J = 7.8 Hz), 6.66 (1H, d, J = 7.8 Hz), 6.64 (1H, t,
J = 7.5 Hz ), 5.84 (1H, br s), 5.10 (2H, s); 13C NMR
(75 MHz, CDCl3) δ 155.9, 145.8, 145.4, 137.5, 136.3,
134.4, 132.3, 129.1, 128.7, 128.5, 128.4, 128.3, 128.2,
124.8, 123.9, 122.2, 118.4, 118.3, 112.8, 67.7, 50.5;
HRMS-ESI m/z [M + H]+ calcd for C28H23BrN3O2:
512.0974, found 512.0961.
4-((((Benzyloxy)carbonyl)amino)(2-phenylimidazo[1,2-a]
pyridin-3-yl)methyl)phenyl acetate (3e). Yield: 51%; Rf =
0.49 (EtOAc/hexane = 1/1); white solid; 1H NMR
(300 MHz, CDCl3) δ 7.66 (2H, d, J = 6.6 Hz), 7.62 (1H,
d, J = 6.9 Hz), 7.55 (1H, d, J = 8.7 Hz), 7.37–7.28 (8H,
m), 7.15 (2H, d, J = 8.4 Hz), 7.10 (1H, td, J = 6.9,
1.2 Hz), 6.98 (2H, d, J = 8.4 Hz), 6.72 (1H, d, J = 7.8 Hz
), 6.47 (1H, t, J = 6.0 Hz), 5.85 (1H, br s), 5.06 (2H, s),
2.25 (3H, s); 13C NMR (75 MHz, CDCl3) δ 168.9, 155.9,
150.5, 145.4, 145.2, 136.2, 135.6, 134.2, 129.0, 128.6,
128.5, 128.2, 128.1, 128.0, 127.4, 124.6, 124.1, 122.1,
118.4, 117.9, 112.5, 67.4, 50.3, 21.2; HRMS-ESI m/z
[M + Na]+ calcd for C30H25N3O4Na: 514.1743, found
514.1752.
Benzyl ((2-Phenylimidazo[1,2-a]pyridin-3-yl)(thiophen-2-
yl)methyl)carbamate (3i). Yield: 50%; Rf = 0.29 (EtOAc/
1
hexane = 1/1); pale yellow color solid; mp 164–166ꢀC; H
NMR (300 MHz, CDCl3) δ 7.80 (1H, d, J = 6.9 Hz), 7.71
(2H, d, J = 6.9 Hz), 7.67 (1H, d, J = 9.0 Hz), 7.42–7.27
(9H, m), 7.19 (1H, td, J = 7.8, 0.9 Hz), 6.93 (1H, t,
J = 3.3 Hz), 6.87 (1H, d, J = 7.8 Hz), 6.78 (1H, d,
J = 3.3 Hz), 6.68 (1H, t, J = 6.3 Hz), 5.95 (1H, br s), 5.05
(2H, s); 13C NMR (75 MHz, CDCl3) δ 155.4, 145.3, 145.1,
142.5, 135.9, 134.0, 129.0, 128.7, 128.6, 128.3, 128.2,
127.6, 126.0, 125.4, 124.9, 124.3, 118.2, 118.1, 112.7,
67.6, 47.8; HRMS-ESI m/z [M + H]+ calcd for
C26H22N3O2S: 440.1433, found 440.1442.
Benzyl (1-(2-Phenylimidazo[1,2-a]pyridin-3-yl)hexyl)car-
bamate (3j). Yield: 31%; Rf = 0.25 (EtOAc/hexane = 1/1);
1
pale yellow color liquid; H NMR (300 MHz, CDCl3) δ
7.66 (2H, d, J = 6.3 Hz), 7.60 (1H, d, J = 8.7 Hz),
7.39–7.27 (9H, m), 7.13 (1H, t, J = 7.8 Hz), 6.73, (1H, d,
J = 7.8 Hz), 5.56 (1H, br s), 5.26 (1H, q, J = 7.8 Hz),
5.04 (2H, s), 1.82 (2H, m), 1.18–1.05 (6H, m), 0.73 (3H, t,
J = 6.9 Hz ); 13C NMR (75 MHz, CDCl3) δ 156.0, 144.6,
144.2, 136.1, 135.0, 129.4, 128.6, 128.4, 128.2, 128.1,
128.0, 124.3, 120.0, 117.8, 112.4, 67.2, 47.6, 33.3, 31.3,
26.2, 22.5, 14.1; HRMS-ESI m/z [M + Na]+ calcd for
C27H29N3O2Na: 450.2157, found 450.2149.
Benzyl ((4-Cyanophenyl)(2-phenylimidazo[1,2-a]pyridin-
3-yl)methyl)carbamate (3f). Yield: 31%; Rf = 0.17
1
(EtOAc/hexane = 1/1); off-white solid; mp 193–195ꢀC; H
NMR (300 MHz, CDCl3) δ 7.64 (2H, d, J = 9.9 Hz),
7.57–7.50 (4H, m), 7.35–7.28 (10H, m), 7.20 (1H, td,
J = 8.1, 0.9 Hz), 6.75 (1H, d, J = 7.8 Hz), 6.69 (1H, t,
J = 6.9 Hz), 5.89 (1H, br d, J = 8.1 Hz ), 5.15 (2H, s);
13C NMR (75 MHz, CDCl3) δ 156.0, 146.0, 145.4, 143.7,
136.0, 133.9, 132.8, 129.0, 128.8, 128.7, 128.6, 128.5,
128.4, 127.2, 125.2, 123.6, 118.4, 118.3, 117.6, 113.1,
112.1, 68.0, 50.5; HRMS-ESI m/z [M + H]+ calcd for
C29H23N4O2: 459.1821, found 459.1807.
Benzyl
((4-Hydroxyphenyl)(2-phenylimidazo[1,2-a]pyri-
din-3-yl)methyl)carbamate (3k). To a stirred solution of 3e
(0.12 g, 0.24 mmol) in MeOH (4 mL) was added K2CO3
(0.07 g, 0.49 mmol) and stirred the mixture at room tem-
perature for 2 h. After completion of the reaction, solvent
was removed under reduced pressure. The crude was neu-
tralized with 1 N HCl and extracted with EtOAc (2 ×
20 mL). Combined organic layer was washed with water
(15 mL), brine (15 mL), dried over anhydrous Na2SO4 and
concentrated in vacuo to afford the pure product 3f (0.08 g,
75%) as white solid. Rf = 0.34 (CH2Cl2/MeOH = 10/1);
Benzyl ((4-Nitrophenyl)(2-phenylimidazo[1,2-a]pyridin-3-
yl)methyl)carbamate (3g). Yield: 41%; Rf = 0.17 (EtOAc/
1
hexane = 1/1); pale yellow solid; mp 188–190ꢀC; H NMR
(300 MHz, CDCl3) δ 8.03 (2H, d, J = 8.7 Hz), 7.62 (1H,
d, J = 6.9 Hz), 7.58 (2H, d, J = 9.3 Hz), 7.54 (1H, d,
J = 6.3 Hz), 7.53 (1H, d, J = 6.3 Hz), 7.33–7.27 (9H, m),
7.17 (1H, t, J = 7.8 Hz), 6.76 (1H, d, J = 7.8 Hz), 6.64
1
mp 213–215ꢀC; H NMR (300 MHz, DMSO) δ 9.51 (1H,
Bull. Korean Chem. Soc. 2017
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C-3 Functionalization of 2-Phenylimidazo[1,2-a]pyridine
KOREAN CHEMICAL SOCIETY
Scheme 2. Synthesis of N-benzyloxycarbonylamino sulfones (1) and 2-phenylimidazo[1,2-a]pyridine (2).
s), 8.74 (1H, d, J = 7.2 Hz), 8.31 (1H, s), 8.14 (1H, d,
J = 6.3 Hz), 7.79 (2H, d, J = 6.3 Hz), 7.64 (1H, d,
J = 9.0 Hz), 7.46–7.23 (8H, m), 6.87 (2H, d, J = 7.8 Hz),
6.80 (1H, t, J = 6.9 Hz), 6.71 (2H, d, J = 6.3 Hz), 6.59
(1H, d, J = 7.8 Hz), 5.01 (2H, q, J = 8.7 Hz); 13C NMR
(75 MHz, DMSO) δ 156.6, 155.9, 144.2, 143.6, 136.7,
134.2, 128.3, 128.2, 127.7, 127.5, 127.1, 125.9, 124.8,
119.0, 116.9, 115.5, 111.7, 65.8, 49.2; HRMS-ESI m/z
[M + H]+ calcd for C28H24N3O3: 450.1818, found
450.1804.
88% aqueous formic acid at 70ꢀC in H2O, like the condi-
tion applied for 1a preparation but 3a formation was not
observed. In addition, 3a obtained in poor yields when the
above 3CR reaction conducted using 10 mol% of
Cu(OTf )2 as a catalyst in DMSO at 100ꢀC for 24 h. The
scope of this reaction was next investigated with a repre-
sentative selection of N-benzyloxycarbonylamino sul-
fones (1).
As shown in Scheme 3, N-benzyloxycarbonylamino sul-
fones (1) derived from various aldehydes (aromatic, hetero-
cyclic, and aliphatic) underwent the present conversion
smoothly (Scheme 3). Aromatic aldehydes containing both
Results and Discussion
We reasoned that C-3 functionalization of 2 could be
achieved by a Lewis-acid catalyzed nucleophilic addition of
2 to the N-acyliminium ions generated from 1. To test this
hypothesis, synthesis of 1a–1j was achieved in high yields
(88–95%) following the literature procedure,15,20 whereas,
2 was obtained in 93% yield by condensation of 2-
aminopyridine and phenacyl bromide, which in turn pro-
cured from acetophenone (Scheme 2). To check the feasi-
bility of our envisioned nucleophilic addition of 2, we
selected 1a (R = Ph) as a model substrate. We scanned a
variety of catalysts for C-3 functionalization of 2 (Table 1).
Cu(OTf )2 (copper(II) trifluoromethanesulfonate) was found
to be the best catalyst for the reaction between 1a and 2 in
DMF (dimethylformamide) at 100ꢀC, affording 3a in 56%
yield (Table 1, entry 6). Changing the reaction solvent to
DMSO increased the yield from 56 to 66% (Table 1, entry
11). Running the reaction without a catalyst resulted in no
product formation and the starting materials were recov-
ered. Other catalysts Bi(OTf )3, Yb(OTf )3, Zn(OTf )3, and
La(OTf )3 also produced 3a in comparable yields (Table 1,
entries 13–16). We were pleased that by utilizing
Cu(OTf )2, the product 3a could be obtained in 24 h. Of
note, several reactions that we tried were significantly
slower and with lower yields when the catalyst loading was
less than 10 mol% and yield improvement was not signifi-
cant when the catalyst loading was more than 10 mol%. In
other solvents such as THF, CH2Cl2, acetonitrile, and ace-
tone lower yields of 3a were noticed. The synthesis of 3a
was also examined via a one-pot three-component reaction
(3CR) between benzaldehyde, benzyl carbamate and 2 using
Table 1. Optimization study for the C-3 functionalization of
2 using 1a.a
Entry
Catalyst
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
No catalyst
InCl3
AlCl3
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
N.R.c
31
27
16
37
56
47
35
42
51
66
36
63
63
64
65
FeCl3
BF3ÁOEt2
Cu(OTf )2
Bi(OTf )3
Yb(OTf )3
Zn(OTf )3
La(OTf )3
Cu(OTf )2
InCl3
Bi(OTf )3
Yb(OTf )3
Zn(OTf )3
La(OTf )3
9
10
11
12
13
14
15
16
a
DMF
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
Reaction conditions: 1a (0.24 mmol), 2 (0.2 mmol), catalyst
(10 mmol%), and solvent (2 mL) at 100ꢀC for 24 h.
Isolated yield.
b
c
No reaction.
Bull. Korean Chem. Soc. 2017
© 2017 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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BULLETIN OF THE
Article
C-3 Functionalization of 2-Phenylimidazo[1,2-a]pyridine
KOREAN CHEMICAL SOCIETY
Scheme 3. Synthesis of C-3 functionalized imidazo[1,2-a]pyridines (3a–k) using N-benzyloxycarbonylamino sulfones (1a–j) and 2-pheny-
limidazo[1,2-a]pyridine (2).
electron-donating and electron-withdrawing groups were
used to prepare the sulfones. Various functional groups
such as methyl, ether, acetoxy, bromo, cyano, and nitro
remained intact. The sulfones derived from an acid sensi-
tive aldehyde such as furfuraldehyde also produced the cor-
responding C-3 functionalized imidazo[1,2-a]pyridine, 3h
in moderate yield. Treatment of imidazo[1,2-a]pyridine, 3e
with K2CO3 in MeOH at room temperature afforded the
phenolic imidazo[1,2-a]pyridine, 3f in 75% yield. Effortless
deprotection of Cbz-(benzyloxycarbonyl) protecting group
in the products 3a–3k under mild conditions is an added
advantage of the protocol. The structures of the products
were established from their spectroscopic (1H NMR, 13C
NMR, ESI-MS, and HRMS) data.
functional groups and having Cbz group, which can be eas-
ily deprotected. We believe that this method could be found
applications in the preparation of functionalized imidazo
[1,2-a]pyridine library for activity screening.
Acknowledgments. This research has been performed as a
cooperation project of “Enhancement of Korea Chemical
Bank” and also supported by the Korea Research Institute
of Chemical Technology (KRICT), South Korea.
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© 2017 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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C-3 Functionalization of 2-Phenylimidazo[1,2-a]pyridine
KOREAN CHEMICAL SOCIETY
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© 2017 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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