Natural α-amino acids applied in the synthesis of imidazo[1,5-a ]N-heterocycles under mild conditions

Article abstract of DOI:10.1021/jo302299u

A facile iodine-mediated decarboxylative cyclization from α-amino acids and N-heterocyclic carbaldehydes was developed. By virtue of this method, a series of imidazo[1,5-a]N-heterocycles can be synthesized efficiently under mild conditions. A tentative re

Full text of DOI:10.1021/jo302299u

Article
pubs.acs.org/joc
Natural α‑Amino Acids Applied in the Synthesis of Imidazo[1,5‑a]N-
heterocycles under Mild Conditions
Qiang Wang, Shuai Zhang, Fengfeng Guo, Baiqun Zhang, Ping Hu, and Zhiyong Wang*
Hefei National Laboratory for Physical Sciences at the Microscale, CAS Key Laboratory of Soft Matter Chemistry and Department of
Chemistry, University of Science and Technology of China, Hefei, Anhui, 230026, P. R. China
S
* Supporting Information
ABSTRACT: A facile iodine-mediated decarboxylative cycli-
zation from α-amino acids and N-heterocyclic carbaldehydes
was developed. By virtue of this method, a series of
imidazo[1,5-a]N-heterocycles can be synthesized efficiently
under mild conditions. A tentative reaction mechanism was
proposed based on the experimental results and previous reports.
INTRODUCTION
■
As an important class of heteroaromatics, imidazo[1,5-a]N-
heterocycles have many applications for their potential
photophysical and biological activities.1 For example, the
imidazo[1,5-a]pyridine skeleton (2-azaindolizines) has poten-
tial applications in organic light-emitting diodes (OLEDs) and
organic thin-layer field effect transistors (FETs).2 Meanwhile,
this structure could also be considered as a precursor for N-
heterocyclic carbene.3 Furthermore, imidazo[1,5-a]quinoline is
an important moiety of NK1 receptor ligands,4a and imidazo-
[1,5-a]quinoxaline is the critical skeleton for inhibitors
targeting phosphodiesterase 10A.4b Despite the significance in
Figure 1. Representative work showing decarboxylative reactions of α-
amino acids involving in situ-generated azomethine ylides.
the above-mentioned areas, only a few synthetic routes are
available for these compounds so far.5,6 The process of these
reported routes mainly relied on traditional Vilsmeier-type
cyclizations of N-2-pyridylmethyl amides. Therefore, alternative
synthetic approaches for imidazo[1,5-a]N-heterocycles are
desired.
Azomethine ylides as active reactants have been widely used
in organic synthesis,7 especially in pericyclic reactions for
heterocycles.8 α-Amino acids have long been recognized as
precursors for active azomethine ylides under some specific
conditions.9 Recently, a series of cascade decarboxylative
reactions involving azomethine ylides have been developed by
Seidel,7e,9e Li,9c,g and Dang/Bai9b to construct C−C and C−N
bonds (Figure 1). On the basis of a similar principle, our group
also developed some decarboxylative cyclization reactions with
primary α-amino acids to prepare pyridines and quinazolines.10
However, transition metals,9c,f,g high temperatures,9a−i and
peroxides9c,d were usually required to enable the decarbox-
ylative activation for the generation of azomethine ylides.
Therefore, the development of facile and mild conditions for
this kind of reaction is still challenging and bears great
significance. As an extension of our research on the
decarboxylative reaction of primary α-amino acids (Figure 2),
herein we report new and efficient methods for the synthesis of
imidazo[1,5-a]N-heterocycles.
Figure 2. Our group’s work: primary α-amino acids participated in
decarboxylative cyclizations involving in situ-generated azomethine
ylides.
Received: October 17, 2012
Published: November 22, 2012
© 2012 American Chemical Society
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KHCO3 was the best, which gave the desired product in 81%
yield (Table 1, entry 10). We also employed phenyl(quinolin-2-
yl)methanone 2b as the reaction substrate for this decarbox-
ylative reaction (Table 1, entries 16−18). However, no desired
product was observed under the selected conditions. Finally,
the optimized reaction conditions were obtained as described
(Table 1, entry 10): 1.0 equiv of aldehyde 2a, 1.1 equiv of α-
amino acid 1a, 1.0 equiv of iodine, 2.0 equiv of KHCO3, and
100 mg of 4 Å MS in 1.5 mL of DMA at 35 °C for 3 h.
With the optimized conditions in hand, the substrate scope
was examined (Table 2). Results indicated that various aliphatic
α-amino acids could be successfully applied in this reaction,
such as Ala (alanine), Glu-5-OMe (glutamic acid 5-methyl
ester), Ile (isoleucine), Leu (leucine), Nor-Leu (nor-leucine),
Val (valine), Nor-Val (nor-valine), Met (methionine), and Phe
(phenylalanine) (Table 2, entries 2−9). Moreover, Thr
(threonine) and Ser (serine), which contain active hydrogens
on the side chains, could also afford the desired products in
satisfactory yields (Table 2, entries 11 and 12). Aromatic α-
amino acids gave better results than aliphatic α-amino acids in
the reactions (Table 2, entries 1−10, 15, and 16), probably
because aromatic rings could stabilize the reaction intermediate
via π-conjugation. Furthermore, the steric hindrance from the
α-amino acid side chains had little influence on the reaction.
For instance, 1c and 1f, bearing large substitutions at the β-
positions, also gave the corresponding products in good yields
although a prolonged reaction time was needed (Table 2,
entries 3 and 5). On the other hand, different N-heterocyclic
carbaldehydes, such as quinoline-2-carbaldehydes, picolinalde-
hydes, quinoxaline-2-carbaldehyde, and isoquinoline-1-carbal-
dehyde, were also examined in this reaction. It was found that
all these N-heterocyclic carbaldehydes provided the corre-
sponding products in good yields (Table 2, entries 13−20).
Furthermore, a weak electronic effect from the different N-
heterocyclic carbaldehydes was observed. In comparison with
the electron-withdrawing substitution, the electron-donating
substitution on the N-heterocyclic carbaldehydes favored this
reaction to some extent (Table 2, entries 13 and 14, 17 and 18).
Compared to the previous reports,9,10 this decarboxylative
cyclization reaction had a much wider substrate scope for α-
amino acids, and many potential optical materials with various
photophysical properties could be obtained by using this
method.
RESULTS AND DISCUSSION
■
Initially, we employed quinoline-2-carbaldehyde 1a and
phenylglycine 2a as model substrates, 20 mol % iodine as
catalyst, and DMA as solvent, and the mixture was stirred at
room temperature for 3 h. The desired products 1-
phenylimidazo[1,5-a]quinoline 3a was obtained in 17% yield
(Table 1, entry 1). In the subsequent optimization, it was found
a
Table 1. Optimization of the Reaction Conditions
yield
b
c
entry
2
catalyst
additive
4 Å MS
temperature
(%)
1
2
2a 20 mol % I2
2a 20 mol % I2
−
rt
17
32
rt
d
3
2a 20 mol % Ag2O 4 Å MS
2a 20 mol % CuBr2 4 Å MS
2a 20 mol % FeCl3 4 Å MS
rt
trace
trace
trace
43
d
4
d
rt
5
rt
6
7
8
9
2a 50 mol % I2
2a 100 mol % I2
2a 100 mol % I2
2a 100 mol % I2
4 Å MS
4 Å MS
4 Å MS
rt
rt
58
35 °C
35 °C
63
4 Å MS/
NaHCO3
75
10
11
12
13
14
15
16
17
18
2a 100 mol % I2
2a 100 mol % I2
2a 100 mol % I2
2a 100 mol % I2
2a 120 mol % I2
2a 150 mol % I2
2b 100 mol % I2
2b 100 mol % I2
2b 50 mol % I2
4 Å MS/KHCO3
4 Å MS/K2CO3
4 Å MS/Et3N
35 °C
35 °C
35 °C
50 °C
35 °C
35 °C
35 °C
80 °C
80 °C
81
71
63
4 Å MS/KHCO3
4 Å MS/KHCO3
4 Å MS/KHCO3
4 Å MS/KHCO3
4 Å MS/KHCO3
4 Å MS/TBHP
73
76
68
n.d.
n.d.
n.d
a
A mixture of L-Phg (0.22 mmol, 1.1 equiv), quinoline-2-carbaldehyde
(0.2 mmol, 1.0 equiv), 1.5 mL of DMA (N,N-dimethylacetamide), and
b
additives was stirred with different catalysts under air for 3 h. 100 mg
c
d
of 4 Å MS, 2.0 equiv of base or TBHP. n. d. = not detected. Reaction
time was 5 h.
that 4 Å MS (molecular sieve) could improve the yield (Table
1, entry 2). Then different potential catalysts were examined. As
shown in Table 1, iodine showed special capability to promote
the reaction, while other metal salts and a metal oxide had no
catalytic activity in this reaction (Table 1, entries 2−5). Cupric
bromide, ferric trichloride, and silver oxide, which have been
frequently employed in decarboxylative reactions, had no
catalytic activity in this reaction (Table 1, entries 3−5). To
further improve the yield, different iodine loadings were
evaluated. With an increase in the iodine loading, the reaction
yield was enhanced (Table 1, entries 2, 6, and 7). When the
loading of iodine was increased to 100 mol %, the reaction yield
was improved to 58% (Table 1, entry 7). However, yields
decreased when more than 1 equiv of iodine was employed
(Table 1, entries 14 and 15). Also, the temperature had an
influence on the reaction. When the temperature was raised to
35 °C, the reaction yield was improved to 63% (Table 1, entry
8). Further increase in the temperature to 50 °C decreased the
yield to 73% with unknown side reactions (Table 1, entry 13).
Experimental results indicated that base could facilitate this
reaction (Table 1, entries 8 and 9). Among the bases examined,
To investigate the reaction mechanism, radical trapping
experiments and an oxygen-free experiment were performed as
control experiments. Two equivalents of radical scavenger was
added to the reaction mixture, and little influence on the
reaction yield was observed (Figure 3 A), which implied that
the decarboxylative pathway did not involve a radical pathway.
As a result, this process is different from that of our previous
work.10b In that case, the decarboxylation process proved to be
a radical reaction. Oxygen-free experiment indicated that this
cascade reaction did not require additional oxidant for the final
aromatization (Figure 3 B).
Based on the results above and the previous reports,9
a
plausible mechanism for the model reaction was proposed
(Scheme 1). The reaction starts from the condensation of
phenylglycine 1a with quinoline-2-carbaldehyde 2a to form
imine I, followed by the N-iodination to give intermediate II.
Subsequently, the intermediate II experiences a KHCO3-
promoted decarboxylative pathway to generate intermediate
IIIa. IIIa can transform to IIIb by tautomerization. And IIIb
can be easily cyclized through an intramolecular nucleophilic
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a
Table 2. Decarboxylative Cyclization of Different α-Amino Acids with N-Heterocyclic Carbaldehydes
a
Reaction scale and conditions: 0.2 mmol N-heterocyclic carbaldehydes, 0.22 mmol of α-amino acids, 0.2 mmol of I2, 0.4 mmol of KHCO3, 1.5 mL
b
c
of DMA, and 100 mg of powder 4 Å MS. Stirred at 35 °C for 3 h. Reaction time 4 h. Room temperature for 4 h.
addition to give IV. Finally, IV loses a hydrogen iodide to give
the final product 3a.
EXPERIMENTAL SECTION
■
Typical Procedure: The Synthesis of 3a. Iodine (51.4 mg, 0.2
mmol) was dissolved in 1.5 mL of DMA, and powdered 4 Å MS (150
mg), potassium bicarbonate (40 mg, 0.4 mmol), L-Phg (33.2 mg, 0.22
mmol), and quinoline-2-carbaldehyde (31.4 mg, 0.2 mmol) were
added. The system was stirred under air at 35 °C, and the reaction
process was monitored by TLC. After 3 h, the system was cooled to
room temperature and extracted with ethyl acetate (3 × 20 mL), and
then the organic layer was washed with brine (2 × 10 mL) and dried
with anhydrous Na2SO4. Subsequently, the solvent was removed and
the product was purified by flash column chromatography (petroleum
ether:ethyl acetate = 10:1) to give 1-phenylimidazo[1,5-a]quinoline
(39.5 mg, 81%) as a light yellow solid.
CONCLUSION
■
In summary, we have developed a facile decarboxylative
cyclization to construct imidazo[1,5-a]N-heterocycles by virtue
of the azomethine ylides generated in situ. With readily
available starting materials, a variety of imidazo[1,5-a]N-
heterocycles containing α-amino acid moieties can be prepared
efficiently. Compared to previous reports, the substrate scope
of the primary α-amino acid was largely extended. In particular,
no metal was required in the reaction, avoiding a metal residue
in the products. Moreover, the compounds constructed by this
methodology bear great research significance for their
potentially photophysical and biological activities.
Substrate Preparation. 6-Bromoquinoline-2-carbaldehyde (2c).
Prepared according to a similar procedure11 from 6-bromo-2-
methylquinoline (302 mg, 1.37 mmol) and purified by column
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acetate:petroleum ether (15:1 v/v) as eluent to give the product as
1
yellow solid (342 mg, 37%), mp = 93−95 °C. H NMR (CDCl3): δ
10.04 (s, 1H), 8.86 (d, J = 1.6 Hz, 1H), 8.04−8.01 (m, 1H), 7.87−7.85
(m, 1H). 13C NMR (CDCl3) δ 191.3, 150.6, 150.3, 138.9, 125.2,
121.7. HRMS(APCI-FTMS) m/z: [M + H]+ calcd for C6H5BrNO
185.9549, found 185.9547.
5-Methylpicolinaldehyde (2h). Prepared according to a proce-
dure12 from 2-bromo-5-methylpyridine (850 mg, 5 mmol), and the
pure product was obtained by column chromatography with ethyl
acetate:petroleum ether (5:1 v/v) as eluent to give the product as
1
yellow solid (248 mg, 41%), mp = 37−39 °C. H NMR (CDCl3): δ
10.05 (s, 1H), 8.62−8.61 (m, 1H), 7.89 (d, J = 8.4 Hz, 1H), 7.69−7.66
(m, 1H), 2.44 (s, 3H). 13C NMR (CDCl3) 193.2, 150.84, 150.81,
138.7, 137.4, 121.4, 18.8. HRMS(APCI-FTMS) m/z: [M + H]+ calcd
for C7H8NO 122.0600, found 122.0593.
Quinoxaline-2-carbaldehyde (2i). 2-Methylquinoxaline (432 mg, 3
mmol) and selenium dioxide (433 mg, 3.9 mmol) were heated at 80
°C in a mixture of dioxane and H2O (5:1 v/v, 12 mL) for 8 h, and the
system was extracted with ethyl acetate, dried over anhydrous sodium
sulfate, concentrated, and purified by column chromatography with
acetate:petroleum ether (1:10 v/v) as eluent to give the product as a
yellow solid (270 mg, 57%), mp = 109−111 °C. 1H NMR (CDCl3):13
δ 10.29 (s, 1H), 9.43 (s, 1H), 8.27−8.20 (m, 2H), 7.97−7.89 (m, 2H).
13C NMR (CDCl3) 192.7, 146.0, 144.5, 142.5, 142.0, 132.9, 131.2,
130.5, 129.7. HRMS(APCI-FTMS) m/z: [M + H]+ calcd for
C9H7N2O 159.0553, found 159.0549.
Analytical and Spectral Data for the Products. 1-
Phenylimidazo[1,5-a]quinoline (3a). Synthesized according to the
typical procedure and purified by column chromatography (petroleum
ether:ethyl acetate = 5:1) to give a light yellow solid (39.5 mg, 81%),
Figure 3. Radical trapping experiments (A) and oxygen-free
experiment (B).
Scheme 1. Proposed Mechanism for the Decarboxylative
Cyclization
1
mp = 113−115 °C. H NMR (CDCl3) δ 7.66−7.61 (m, 2H), 7.61−
7.58 (m, 2H), 7.53−7.49 (m, 4H), 7.33−7.27 (m, 2H), 7.18−7.13 (m,
1H), 7.01−6.69 (d, J = 8.4 Hz, 1H). 13C NMR (CDCl3) δ 142.5,
133.9, 132.4, 130.6, 129.7, 129.3, 128.8, 128.7, 127.4, 125.7, 125.2,
122.5, 121.5, 117.5, 117.2. HRMS(APCI-FTMS) m/z: [M + H]+ calcd
for C17H13N2 245.1073, found 245.1076. IR (cm−1) ν 2956, 2920,
1454, 1371, 812, 754.
1-Methylimidazo[1,5-a]quinoline (3b). Synthesized according to
typical procedure and purified by column chromatography (petroleum
ether:ethyl acetate = 5:1) to give a light yellow oil (22.5 mg, 62%). 1H
NMR (CDCl3) δ 8.18−8.16 (d, J = 8.4 Hz, 1H), 7.61−7.59 (m, 1H),
7.50−7.45 (m, 1H), 7.38−7.34 (m, 1H), 7.30 (s, 1H), 7.23−7.20 (d, J
= 9.6 Hz, 1H), 6.90−6.88 (d, J = 8.8 Hz, 1H), 3.05 (s, 3H). 13C NMR
(CDCl3) δ 139.1, 132.4, 129.4, 127.6, 126.8, 124.8, 123.9, 119.6, 119.6,
116.4, 115.2, 18.6. HRMS(APCI-FTMS) m/z: [M + H]+ calcd for
C12H11N2 183.0917, found 183.0916. IR (cm−1) ν 2954, 2923, 1453,
1385, 808, 754.
1-sec-Butylimidazo[1,5-a]quinoline (3c). Synthesized according to
the typical procedure but extending the reaction time to 4 h and
purified by column chromatography (petroleum ether:ethyl acetate =
1
8:1) to give a light yellow oil (32.3 mg, 72%). H NMR (CDCl3) δ
chromatography on silica gel with ethyl acetate:petroleum ether (1:20
v/v) as eluent to give the product as yellow solid (231 mg, 72%), mp =
143−145 °C. 1H NMR (CDCl3): δ 10.20 (s, 1H), 8.24 (d, J = 8.4 Hz,
1H), 8.13−8.04 (m, 3H), 7.91−7.88 (m, 1H). 13C NMR (CDCl3) δ
193.4, 152.9, 146.6, 136.4, 134.2, 132.1, 131.1, 130.1, 123.7, 118.3.
HRMS(APCI-FTMS) m/z: [M + H]+ calcd for C10H7BrNO 235.9706,
found 235.9703.
8.14−8.12 (d, J = 8.4 Hz, 1H), 7.62−7.60 (m, 1H), 7.52−7.48 (m,
1H), 7.38−7.34 (m, 2H), 7.25−7.22 (d, J = 9.2 Hz, 1H), 3.62 −3.57
(m, 1H), 2.21−2.14 (m, 1H), 1.84−1.77 (m, 1H), 1.54 (d, J = 6.0 Hz,
3H), 1.04 (t, J = 6.4 Hz, 3H). 13C NMR (CDCl3) δ 148.8, 133.3,
130.2, 128.8, 127.7, 126.2, 124.8, 120.9, 120.6, 117.6, 117.0, 36.8, 28.6,
19.0, 12.0. HRMS(APCI-FTMS) m/z: [M + H]+ calcd for C15H17N2
225.1386, found 225.1382. IR (cm−1) ν 2964, 2928, 1473, 1453, 809,
753.
8-Methoxyquinoline-2-carbaldehyde (2d). Prepared according to
a procedure11 from 6-bromo-2-methylquinoline (1.38 g, 8 mmol) and
purified by column chromatography on silica gel with ethyl
acetate:petroleum ether (1:5 v/v) as eluent to give the product as
1-Isobutylimidazo[1,5-a]quinoline (3d). Synthesized according to
the typical procedure and purified by column chromatography
(petroleum ether:ethyl acetate = 5:1) to give a light yellow oil (32.7
1
yellow solid (1.17 g, 78%), mp = 101−103 °C. H NMR (CDCl3): δ
1
mg, 73%). H NMR (CDCl3) δ 8.10 (d, J = 8.4 Hz, 1H), 7.62−7.60
10.33 (s, 1H), 8.31 (d, J = 8.4 Hz, 1H), 8.09 (d, J = 8.4 Hz, 1H), 7.65−
7.61 (m, 1H), 7.50−7.48 (m, 1H), 7.17 (d, J = 7.6 Hz, 1H), 4.17 (s,
3H). 13C NMR (CDCl3) δ 193.7, 156.2, 151.6, 140.0, 137.4, 131.4,
129.9, 119.7, 118.0, 56.4. HRMS(APCI-FTMS) m/z: [M + H]+ calcd
for C11H10NO2 188.0706, found 188.0702.
(m, 1H), 7.52−7.48 (m, 1H), 7.38−7.34 (m, 2H), 7.25 (d, J = 9.6 Hz,
1H), 6.91 (d, J = 9.6 Hz, 1H), 3.25 (d, J = 6.8 Hz, 2H), 2.42−2.39 (m,
1H), 1.09 (d, J = 6.8 Hz, 6H). 13C NMR (CDCl3) δ 143.5, 133.2,
130.4, 128.7, 127.7, 126.0, 124.9, 120.8, 120.6, 117.5, 116.6, 41.2, 26.6,
22.7. HRMS(APCI-FTMS) m/z: [M + H]+ calcd for C15H17N2
225.1386, found 225.1383 IR (cm−1) ν 2955, 2867, 1471, 1383,
809, 753.
5-Bromopicolinaldehyde (2g). Prepared according to a proce-
dure12 from 2,5-dibromopyridine (1.18 g, 5 mmol), and the pure
product was obtained by column chromatography with ethyl
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1-Isopropylimidazo[1,5-a]quinoline (3e). Synthesized according to
the typical procedure but extending the reaction time to 4 h and
purified by column chromatography (petroleum ether:ethyl acetate =
(s, 2H). 13C NMR (CDCl3) δ 142.5, 132.6, 131.1, 128.8, 128.6, 125.6,
125.5, 122.0, 120.4, 117.9, 117.0, 59.2. HRMS(APCI-FTMS) m/z: [M
+ H]+ calcd for C12H11N2O 199.0866, found 199.0863. IR (cm−1) ν
3310, 2957, 2925, 1452, 811, 733.
1
5:1) to give a light yellow oil (29.8 mg, 71%). H NMR (CDCl3) δ
8.17 (d, J = 8.4 Hz, 1H), 7.62−7.60 (m, 1H), 7.52−7.48 (m, 1H),
7.38−7.34 (m, 4H), 7.25 (d, J = 9.2 Hz, 1H), 6.91 (d, J = 9.2 Hz, 1H),
3.84−3.79 (m, 1H), 1.57 (d, J = 6.8 Hz, 6H). 13C NMR (CDCl3) δ
149.5, 133.2, 130.3, 128.8, 127.8, 126.1, 124.8, 120.8, 120.6, 117.6,
117.0, 30.1, 21.7. HRMS(APCI-FTMS) m/z: [M + H]+ calcd for
C14H15N2 211.1230, found 211.1229. IR (cm−1) ν 2968, 2926, 1475,
1453, 809, 754.
1-Propylimidazo[1,5-a]quinoline (3f). Synthesized according to the
typical procedure and purified by column chromatography (petroleum
ether:ethyl acetate = 5:1) to give a light yellow oil (28.9 mg, 69%). 1H
NMR (CDCl3) δ 8.13 (d, J = 8.4 Hz, 1H), 7.62−7.60 (m, 1H), 7.52−
7.48 (m, 1H), 7.38−7.34 (m, 2H), 7.24 (d, J = 9.2 Hz, 1H), 6.91 (d, J
= 9.2 Hz, 1H), 3.35−3.31 (m, 2H), 2.07−1.98 (m, 2H), 1.15−1.12 (m,
3H). 13C NMR (CDCl3) δ 144.1, 133.3, 130.3, 128.7, 127.8, 125.9,
124.8, 120.8, 120.6, 117.5, 116.6, 34.5, 20.6, 14.1. HRMS(APCI-
FTMS) m/z: [M + H]+ calcd for C14H15N2 211.1230, found 211.1232.
IR (cm−1) ν 2959, 2870, 1453, 1389, 807, 753.
1-Butylimidazo[1,5-a]quinoline (3g). Synthesized according to the
typical procedure and purified by column chromatography (petroleum
ether:ethyl acetate = 5:1) to give a light yellow oil (31.8 mg, 71%). 1H
NMR (CDCl3) δ 8.13 (d, J = 8.4 Hz, 1H), 7.62−7.60 (m, 1H), 7.52−
7.48 (m, 1H), 7.38−7.34 (m, 2H), 7.24 (d, J = 9.2 Hz, 1H), 6.91 (d, J
= 9.2 Hz, 1H), 3.37−3.33 (m, 2H), 2.02−1.94 (m, 2H), 1.59−1.53 (m,
2H), 1.04−1.00 (m, 2H). 13C NMR (CDCl3) δ 144.3, 133.3, 130.3,
128.7, 127.8, 125.9, 124.9, 120.7, 120.6, 117.5, 116.6, 32.2, 29.4, 22.7,
14.0. HRMS(APCI-FTMS) m/z: [M + H]+ calcd for C15H17N2
225.1386, found 225.1382. IR (cm−1) ν 2955, 2869, 1453, 1389,
808, 753.
Methyl 3- (Imidazo[1,5-a]quinolin-1-yl)propanoate (3h). Synthe-
sized according to the typical procedure and purified by column
chromatography (petroleum ether:ethyl acetate = 5:1) to give a light
yellow solid (29.5 mg, 58%), mp = 101−103 °C. 1H NMR (CDCl3) δ
8.19 (d, J = 8.4 Hz, 1H), 7.63−7.61 (m, 1H), 7.53−7.49 (m, 1H),
7.39−7.33 (m, 2H), 7.24 (d, J = 9.2 Hz, 1H), 6.93 (d, J = 9.2 Hz, 1H),
3.75 (s, 3H), 3.68−3.65 (m, 2H), 3.15−3.11 (m, 2H). 13C NMR
(CDCl3) δ 173.5, 142.1, 133.2, 130.7, 128.7, 127.9, 125.9, 125.0, 120.9,
120.8, 117.4, 116.6, 52.0, 31.4, 27.8. HRMS(APCI-FTMS) m/z: [M +
H]+ calcd for C15H15N2O2 255.1128, found 255.1127. IR (cm−1) ν
2950, 2923, 1737, 1452, 1168, 809, 756.
1-(Imidazo[1,5-a]quinolin-1-yl)ethanol (3l). Synthesized according
to the typical procedure and purified by column chromatography
(petroleum ether:ethyl acetate = 2:1) to give a light yellow solid (23.7
1
mg, 56%), mp = 109−111 °C. H NMR (CDCl3) δ 8.46 (d, J = 8.4
Hz, 1H), 7.64−7.62 (m, 1H), 7.58−7.54 (m, 1H), 7.43−7.41 (m, 1H),
7.26 (s, 1H), 7.21 (d, J = 9.6 Hz, 1H), 6.99 (d, J = 9.2H, 1H), 5.54−
5.49 (m, 1H), 3.23 (s, 1H), 1.87 (d, J = 6.4 Hz, 3H). 13C NMR
(CDCl3) δ 145.6, 132.6, 131.0, 128.6, 128.5, 125.7, 125.4, 121.7, 120.2,
118.4, 117.0, 64.6, 22.6. HRMS(APCI-FTMS) m/z: [M + H]+ calcd
for C13H13N2O 213.1022, found 213.1020. IR (cm−1) ν 3207, 2957,
2869, 1453, 1370, 1088, 811, 756.
7-Bromo-1-phenylimidazo[1,5-a]quinoline (3m). Synthesized ac-
cording to the typical procedure and purified by column
chromatography (petroleum ether:ethyl acetate = 5:1) to give a light
yellow solid (43.8 mg, 68%), mp = 128−130 °C. 1H NMR (CDCl3) δ
7.73 (d, J = 2.4 Hz, 1H), 7.63−7.59 (m, 2H), 7.55 (s, 1H), 7.53−7.50
(m, 3H), 7.37−7.34 (m, 2H), 7.35−7.23 (m, 1H), 6.92 (d, J = 9.6 Hz,
1H). 13C NMR (CDCl3) δ 142.7, 133.5, 131.3, 130.8, 130.4, 130.1,
129.6, 129.6, 129.0, 127.5, 123.1, 120.3, 119.0, 118.6, 118.4.
HRMS(APCI-FTMS) m/z: [M + H]+ calcd for C17H17BrN2
323.0178, found 323.0175. IR (cm−1) ν 2954, 2919, 1470, 1454,
1373, 816, 761.
9-Methoxy-1-phenylimidazo[1,5-a]quinoline (3n). Synthesized
according to typical procedure and purified by column chromatog-
raphy (petroleum ether:ethyl acetate = 8:1) to give a light yellow solid
(41.6 mg, 76%), mp = 115−117 °C. 1H NMR (CDCl3) δ 7.56 (s, 1H),
7.53−7.50 (m, 2H), 7.38−7.34 (m, 2H), 7.32−7.28 (m, 2H), 7.26 (d, J
= 4.0 Hz, 1H), 7.21−7.18 (m, 1H), 6.93 (d, J = 9.6 Hz, 1H), 6.78−
6.76 (m, 1H), 3.01 (s, 1H). 13C NMR (CDCl3) δ 149.2, 146.8, 136.5,
131.8, 128.6, 128.0, 127.6, 126.0, 125.1, 123.0, 122.5, 120.9, 119.5,
117.8, 109.9, 53.7. HRMS(APCI-FTMS) m/z: [M + H]+ calcd for
C18H15N2O 275.1179, found 275.1177. IR (cm−1) ν 2958, 2928, 1469,
1271, 819, 767.
3-Phenylimidazo[1,5-a]pyridine (3o). Synthesized according to the
typical procedure but changing the reaction temperature to room
temperature and maintaining for 4 h. Purified by column
chromatography (petroleum ether:ethyl acetate = 5:1) to give a light
yellow solid (27.9 mg, 72%), mp = 107−109 °C. 1H NMR (CDCl3) δ
8.25−8.23 (m, 1H), 7.80−7.77 (m, 2H), 7.55−7.39 (m, 5H), 6.72−
6.70 (m, 1H), 6.55−6.52 (m, 1H). 13C NMR (CDCl3) δ 138.3, 131.7,
130.5, 129.0, 128.7, 128.0, 121.5, 120.7, 118.9, 118.8, 113.1.
HRMS(APCI-FTMS) m/z: [M + H]+ calcd for C13H11N2 195.0917,
found 195.0915. IR (cm−1) ν 2955, 2921, 1644, 1462, 722.
1-Benzylimidazo[1,5-a]quinoline (3i). Synthesized according to the
typical procedure and purified by column chromatography (petroleum
ether:ethyl acetate = 8:1) to give a light yellow solid (38.7 mg, 75%),
mp = 95−97 °C. 1H NMR (CDCl3) δ 7.98−7.96 (m, 1H), 7.57−7.55
(m, 1H), 7.32−7.24 (m, 5H), 7.21−7.13 (m, 3H), 6.94 (d, J = 9.2 Hz,
1H), 4.80 (s, 2H). 13C NMR (CDCl3) δ 141.5, 137.0, 132.6, 130.8,
128.9, 128.5, 128.3, 127.8, 126.8, 125.7, 125.0, 121.4, 121.0, 117.3,
116.9, 37.9. HRMS(APCI-FTMS) m/z: [M + H]+ calcd for C18H15N2
259.1230, found 259.1227. IR (cm−1) ν 2923, 2851, 1453, 1386, 811,
721.
3-Isobutylimidazo[1,5-a]pyridine (3p). Synthesized according to
the typical procedure but changing the reaction temperature to room
temperature and maintaining for 4 h. Purified by column
chromatography (petroleum ether:ethyl acetate = 8:1) to give a light
1
yellow oil (21.6 mg, 62%). H NMR (CDCl3) δ 7.74−7.72 (m, 1H),
7.41−7.38 (m, 1H), 7.36 (s, 1H), 6.64−6.60 (m, 1H), 6.53−6.49 (m,
1H), 2.85 (d, J = 7.2 Hz, 2H), 2.28−2.21 (m, 1H), 1.0 (d, J = 7.2 Hz,
6H). 13C NMR (CDCl3) δ 138.5, 130.3, 120.7, 118.7, 118.5, 117.6,
112.2, 35.7, 27.7, 22.7. HRMS(APCI-FTMS) m/z: [M + H]+ calcd for
C11H15N2 174.1230, found 174.1227. IR (cm−1) ν 2956, 2929, 1465,
1364, 1038, 785, 731.
1-(2-(Methylthio)ethyl)imidazo[1,5-a]quinoline (3j). Synthesized
according to the typical procedure and purified by column
chromatography (petroleum ether:ethyl acetate = 5:1) to give a light
1
yellow solid (34.4 mg, 71%), mp = 71−73 °C. H NMR (CDCl3) δ
8.11 (d, J = 8.4 Hz, 1H), 7.64−7.62 (m, 1H), 7.52−7.50 (m, 1H),
7.40−7.35 (m, 2H), 7.25 (d, J = 9.2 Hz, 1H), 6.94 (d, J = 9.2 Hz, 1H),
3.67−3.63 (m, 2H), 3.19−3.15 (m, 2H), 2.24 (s, 3H). 13C NMR
(CDCl3) δ 142.1, 133.0, 130.5, 128.8, 128.0, 125.9, 125.1, 120.9, 117.4,
116.4, 32.9, 31.5, 16.0. HRMS(APCI-FTMS) m/z: [M + H]+ calcd for
C14H15N2S 243.0950, found 243.0946. IR (cm−1) ν 2960, 2918, 1474,
1389, 808, 754.
6-bromo-3-phenylimidazo[1,5-a]pyridine (3q). Synthesized ac-
cording to the typical procedure but changing the reaction
temperature to room temperature and maintaining for 4 h. Purified
by column chromatography (petroleum ether:ethyl acetate = 8:1) to
1
give a light yellow solid (35.7 mg, 66%), mp = 81−83 °C. H NMR
(CDCl3) δ 8.38−8.36 (m, 1H), 7.77−7.74 (m, 2H), 7.56−7.51 (m,
3H), 7.47−7.43 (m, 1H), 7.39−7.36 (m, 1H), 6.77−6.74 (m, 1H). 13C
NMR (CDCl3) δ 138.7, 130.0, 129.8, 129.2, 129.1, 128.0, 122.4, 122.0,
121.3, 119.4, 108.9. HRMS(APCI-FTMS) m/z: [M + H]+ calcd for
C13H10BrN2 273.0022, found 273.0018. IR (cm−1) ν 2955, 2922, 1625,
1456, 1328, 909, 763.
Imidazo[1,5-a]quinolin-1-ylmethanol (3k). Synthesized according
to the typical procedure and purified by column chromatography
(petroleum ether:ethyl acetate = 2:1) to give a light yellow solid (20.6
mg, 52%), mp = 113−115 °C. H NMR (CDCl3) δ 8.44 (d, J = 8.4
Hz, 1H), 7.68−7.66 (m, 1H), 7.63−7.59 (m, 1H), 7.46−7.42 (m, 1H),
7.31 (s, 1H), 7.27 (d, J = 8.4 Hz, 1H), 7.05 (d, J = 9.6 Hz, 1H), 5.26
1
11165
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The Journal of Organic Chemistry
Article
6-Methyl-3-phenylimidazo[1,5-a]pyridine (3r). Synthesized ac-
cording to typical procedure but changing the reaction temperature
to room temperature and maintaining for 4 h. Purified by column
chromatography (petroleum ether:ethyl acetate = 5:1) to give a light
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1
yellow solid (30.4 mg, 73%), mp = 71−73 °C. H NMR (CDCl3) δ
8.03−8.01 (m, 1H), 7.79−7.76 (m, 2H), 7.53−7.48 (m, 3H), 7.43−
7.37 (m, 2H), 6.58−6.56 (m, 1H), 2.21 (d, J = 1.2 Hz, 3H). 13C NMR
(CDCl3) δ 137.8, 130.9, 130.7, 129.0, 128.5, 128.0, 122.6, 122.4, 120.5,
118.5, 118.1, 18.6. HRMS(APCI-FTMS) m/z: [M + H]+ calcd for
C14H13N2 209.1073, found 209.1069. IR (cm−1) ν 2923, 2853, 1602,
1454, 805, 768.
1-Phenylimidazo[1,5-a]quinoxaline (3s). Synthesized according to
typical procedure and purified by column chromatography (petroleum
ether:ethyl acetate = 5:1) to give a light yellow solid (41.6 mg, 85%),
mp = 114−116 °C. 1H NMR (CDCl3) δ 8.91 (s, 1H), 7.96−7.94 (m,
1H), 7.90 (s, 1H), 7.69−7.65 (m, 2H), 7.59−7.53 (m, 3H), 7.51−7.49
(m, 2H), 7.45−7.43 (m, 1H), 7.24−7.19 (m, 1H). 13C NMR (CDCl3)
δ 145.5, 143.7, 137.2, 132.3, 130.3, 130.1, 129.7, 129.0, 127.7, 127.0,
126.8, 126.7, 126.0, 116.6. HRMS(APCI-FTMS) m/z: [M + H]+ calcd
for C16H12N3 246.1026, found 246.1024. IR (cm−1) ν 2955, 2918,
1454, 1385, 1261, 796.
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Cycloaddition Chemistry Toward Heterocycles and Natural Products;
Wiley: Chichester, U.K., 2002; Vol. 59, p 940. (b) Coldham, I.;
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1278.
3-Phenylimidazo[5,1-a]isoquinoline (3t). Synthesized according to
typical procedure and purified by column chromatography (petroleum
ether:ethyl acetate = 5:1) to give a light yellow solid (43.9 mg, 90%),
mp = 137−139 °C. 1H NMR (CDCl3) δ 8.01−7.99 (m, 1H), 7.96 (d,
J = 7.6 Hz, 1H), 7.90 (d, J = 7.6 Hz, 1H), 7.77−7.74 (m, 2H), 7.52−
7.41 (m, 5H), 7.39−7.37 (m, 1H), 7.72 (d, J = 7.6 Hz, 1H). 13C NMR
(CDCl3) δ 141.0, 130.2, 129.4, 129.0, 128.9, 128.45, 128.42, 126.99,
126.97, 125.1, 122.4, 120.8, 120.6, 113.9. HRMS(APCI-FTMS) m/z:
[M + H]+ calcd for C17H13N2 245.1073, found 245.1071. IR (cm−1)
2954, 2921, 1449, 1369, 793, 702.
ν
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ASSOCIATED CONTENT
■
S
* Supporting Information
1H NMR and 13C NMR spectra for all the products. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: zwang3@ustc.edu.cn
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to the National Natural Science Foundation of
China (No. 21272222, 21172205, 20772118, 20932002,
20972144, J1030412) for the support.
REFERENCES
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