Synthesis of 1,3-Disubstituted Imidazo[1,5-a]pyridines from Amino Acids via Catalytic Decarboxylative Intramolecular Cyclization

Article abstract of DOI:10.1021/acs.joc.6b00343

A copper/iodine cocatalyzed decarboxylative cyclization of α-amino acids is described. Starting from the readily available amino acids and either 2-benzoylpyridines or 2-benzoylquinolines, 1,3-disubstituted imidazo[1,5-a]pyridines and 1,3-disubstituted im

Full text of DOI:10.1021/acs.joc.6b00343

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Article
Synthesis of 1,3-disubstituted imidazo[1,5-a]pyridines from amino
acids via catalytic decarboxylative intramolecular cyclization
Huiqiao Wang, Wentao Xu, Lilan Xin, Wenmin Liu, Zhiqiang Wang, and Kun Xu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b00343 • Publication Date (Web): 05 Apr 2016
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Synthesis of 1,3-disubstituted imidazo[1,5-a]pyridines from amino acids via catalytic
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decarboxylative intramolecular cyclization
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Huiqiao Wang, Wentao Xu, Lilan Xin, Wenmin Liu, Zhiqiang Wang* and Kun Xu*
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College of Chemistry and Pharmaceutical Engineering, Nanyang Normal University, Nanyang, Henan, 473061, P. R. China
E-mail: xukun@nynu.edu.cn; smile_126@qq.com
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Abstract: A copper/iodine co-catalyzed decarboxylative cyclization of α-amino acids is described. Starting from the readily available
amino acids and either 2-benzoylpyridines or 2-benzoylquinolines, 1,3-disubstituted imidazo[1,5-a]pyridines and 1,3-disubstituted
imidazo[1,5-a]quinolines were prepared in excellent yields.
Introduction: Transition-metal catalyzed decarboxylation reactions have attracted much attention for their use in the site-specific
introduction of functional groups.1 Compared to other carboxylic acids, α-amino acids have the advantages of natural abundant, high
stability and low cost, which make them extremely promising raw materials for chemical synthesis. Therefore, α-amino acids have been
widely used to construct C-C,2 C-N3 and C-O4 bonds via a decarboxylative coupling process. While various decarboxylation reaction of
amino acids have been well-studied, new decarboxylative cyclization of α-amino acids for the synthesis of biologically important
heterocycles, especially in a catalytic manner, is still highly desirable.
Imidazo[1,5-a]pyridine scaffolds are present in various drug-relevant molecules and biologically active agents.5 Thus, method
development for accessing this important structural motif is of high interest. Traditionally, imidazo[1,5-a]pyridines were prepared through
Vilsmeier-type cyclizations or their variants.6 Recent efforts on the oxidative cyclization reaction also provided a complementary way to
access imidazo[1,5-a]pyridines.7,8 However, most of these methods were ineffective for the construction of 1,3-disubstituted imidazo[1,5-
a]pyridines.9 To address this limition, our group recently developed an oxidative amination method to give 1,3-diarylimidazo[1,5-
a]pyridine in excellent yields (Scheme 1A).10 Unfortunately, the complementary 3-alkyl derivatives were not accessible via this oxidative
amination process. In continuation of our recent work on decarboxylation reaction of amino acids,4c we report herein an efficient
decarboxylative cyclization of amino acids for the synthesis of 3-alkyl-1-arylimidazo[1,5-a]pyridines (Scheme 1B). To the best of our
knowledge, successful example on the synthesis of this type of scaffold is rather limited.11
Scheme 1. Our methods for the synthesis of 1,3-disubstituted imidazo[1,5-a]pyridines
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Results and Discussion: Previous work reported by Li et al. has shown that the combination of copper salt with peroxide was
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effective for the decarboxylation of amino acids.2a To identify the best reaction conditions, the decarboxylative cyclization reaction
between 2-benzoylpyridine 1a and leucine 2a was tested under different oxidative reaction conditions (Table 1). First, the efficiency of
different copper salts was screened with molecular iodine as a cocatalyst. The results showed that Cu(OTf)2 was the most efficient catalyst
for this reaction (entry 1); while other copper catalysts resulted in a significant drop in yields (entries 2-5). In the absence of copper
catalysts, the reaction gave the target product 3a in 39% yield (entry 6), while only 20% yield of the desired product was obtained in the
absence of molecular iodine (entry 7). Subsequently, n-Bu4NI instead of molecular iodine as a catalyst was tested, however, the yield of
product 3a decreased to 51% (entry 8). Then, the influence of different peroxide on this decarboxylative cyclization reaction was
investigated. The results revealed that DTBP (di-t-butyl peroxide) would be the best choice for this reaction (entries 1 vs 9-10). Further
assessment of the reaction conditions indicated that toluene was the optimal solvent; while other commonly used solvents gave lower
yields (entries 1 vs 11-14). By increasing or lowing the reaction temperature, no improvement in yield was observed (entries 15-16).
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Table 1 Optimization of the reaction conditionsa
a Reaction conditions: 1a (0.3 mmol), 2a (0.9 mmol), copper salt (0.045 mmol), I2 (0.045 mmol), oxidant (0.75 mmol) in solvent (1 mL), 120 oC , 10h.
DTBP= di-tert- butyl peroxide; TBHP= tert-butyl hydroperoxide; BPO= dibenzoyl peroxide. b Isolated yield. c no molecular iodine was used. d n-Bu4NI was
used instead of iodine. e the reaction temperature was 130 oC. f the reaction temperature was 100 oC.
Having identified the optimal reaction conditions, we next examined the substrate scope of this decarboxylative cyclization reaction by
evaluating a variety of 2-benzoylpyridine derivatives 1. As shown in Table 2, this cyclization reaction is relatively unaffected by the nature
of the aryl group, with substrates bearing electron donating or withdrawing functionalities demonstrating excellent efficiency (entries 1-4).
However, the ortho-substituted aryl group led to a decrease in the yield (entry 5), while meta-substituted aryl groups had little influence on
the yield (entries 6-9). When aryl group was replaced to the bulky 1-naphthyl group, the decarboxylation reaction furnished the cyclized
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product 3j in 82% yield (entry 10). In addition, when 2-benzoyl quinoline was employed as the substrate, the corresponding product 3k
was obtained in 81% yield (entry 11). However, when 1-(pyridin-2-yl)ethanone was employed as the substrate, no corresponding product
was detected (entry 12).
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Table 2 The substrate scope of pyridine ketonesa
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Reaction conditions: 1 (0.3 mmol), 2a (0.9 mmol), Cu(OTf)2 (0.045 mmol), I2 (0.045 mmol), DTBP (0.75 mmol) in toluene (1 mL), 120 oC , 10h.
Isolated yield.
Under the optimal reaction conditions, we next sought to establish the scope of aliphatic amino acids in this decarboxylative cyclization
reaction. As shown in Table 3, a range of linear and branched amino acids were successfully employed in this reaction to give the products
4a-4d in moderate to good yields. For the linear amino acids, alanine and norvaline provided the desired products 4a-4b with similar level
of yields (entries 1-2), while the bulky norleucine led to a decrease of the yields (entry 3). For the branched amino acid, isoleucine was
also tolerated well under the optimal reaction conditions to give product 4d in 83% yield (entry 4).
Table 3 The substrate scope of aliphatic amino acidsa
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a Reaction conditions: 1a (0.3 mmol), 2 (0.9 mmol), Cu(OTf)2 (0.045 mmol), I2 (0.045 mmol), DTBP (0.75 mmol) in toluene (1 mL), 120 oC , 10h. b
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Isolated yield.
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To further extend the utility of this decarboxylative cyclization reaction, we next turned our attention to the reaction of 2-
benzoylpyridines with α-aryl-substituted amino acids (Table 4). First, various 2-benzoylpyridines were employed as substrates to react
with phenylglycine under the optimal conditions. The results showed that 2-benzoylpyridines were excellent substrates regardless of the
electronic nature of the aryl substituents, giving 1, 3-diarylimidazo[1,5-a]pyridines 6a-6m in good to excellent yields (entries 1-13).
Besides, 2-benzoylquinoline was also successfully employed as a substrate to give the corresponding product 6n in 84% yield (entry 14).
Finally, some other α-aryl-substituted amino acids were employed as substrates to react with 2-benzoylpyridine. The results showed that
para-, and meta-halogenated phenylglycines were all compatible with the standard reaction conditions (entries 15-17).
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Table 4 The substrate scope of the reaction between 2-benzoylpyridines and phenylglycine derivatives a
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Reaction conditions: 1 (0.3 mmol), 2a (0.9 mmol), Cu(OTf)2 (0.045 mmol), I2 (0.045 mmol), DTBP (0.75 mmol) in toluene (1 mL), 120 C , 10h.
Isolated yield.
To probe the nature of this decarboxylative cyclization reaction, the radical-trapping reagent (TEMPO) was subjected into the reaction
of 1a with 2a under the standard conditions (Scheme 2). The desired product 3a was obtained in 73% yield, suggesting an ionic pathway
was most probably involved in this decarboxylation reaction.
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Scheme 2. Control experiment
In our previous work, benzylamine could react with 2-benzoylpyridine to afford imidazo[1,5-a]pyridine.10 To determine whether amine
was the intermediate of this reaction, the competitive experiment with phenylglycine and 4-fluorobenzylamine was carried out in the same
reaction flask (Scheme 3). It was found that 4-fluorobenzylamine gave the corresponding product 8 in only 9% yield, which suggested that
amine was not likely to be the intermediate of this decarboxylation reaction.
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Scheme 3. Competitive reaction between phenylglycine and 4-fluorobenzylamine
On the basis of the control experiment and previous reports,10-14 a plausible mechanism was proposed as shown in Scheme 4. First, the
condensation reaction between 2-benzoylpyridine 1a and amino acid generates imine A. The nitrogen source in the reaction mixture (could
be any of the pyridine/amine/imine species) acts as a base to deprotonate imine A to generate an organic acid anion, which then reacts with
copper salt to give copper carboxylate B.12 In the structure of intermediate B, two five-membered chelates were formed upon metal
binding. Subsequently, intermediate B undergoes a decarboxylation reaction to afford intermediate C, which then undergoes an oxidative
iodination to give intermediate D. With the assistance of iodide anion, the copper-carbon bond in intermediate D could dissociate to
generate azomethine ylide-type intermediate E2a,13. Then, the elimination of iodide anion furnishes intermediate F,10-11 which could
tautomerize to intermediate G. Intermediate G will not violate the geometric constrains imposed by the intermediate F. Finally, the
intramolecular amination of intermediate G leads to the formation of cyclised intermediate H,14 which then undergoes an oxidative
dehydrogenation and rearrangement to yield product 3.
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Scheme 4. A plausible mechanism for the formation of product 3.
Conclusion: In conclusion, we have developed an efficient copper/iodine cocatalytic system for the decarboxylative cyclization of α-
amino acids with 2-benzoylpyridines. The present decarboxylative cyclization reaction not only provided an attractive alternative method
for the synthesis of 1,3-diarylimidazo[1,5-a]pyridines, but also opened a new route to construct 3-alkyl-1-arylimidazo[1,5-a]pyridines,
which are difficult to access by the existing methods.
Experimental Section
General methods. NMR spectra were recorded on 300 MHz or 400 MHz NMR spectrometer with CDCl3 as the solvent and
tetramethylsilane (TMS) as the internal standard. HRMS was obtained by Electrospray Ionization (ESI) on a TOF mass analyzer. Melting
points were determined on a melting point apparatus and are uncorrected. Pyridine ketones 1 were prepared by using the same methods
described in our previous report.10 Amino acids were commercially available and were used without further purification.
General procedure for the synthesis of 1, 3-disubstituted imidazo[1,5-a]pyridines (Tables 2-4). To a sealed tube (10 mL) containing a
solution of 2-benzoylpyridine 1a (0.3 mmol) in Tol (1.0 mL) was added Cu(OTf)2 (0.045 mmol), molecular iodine(0.045 mmol), DTBP
(0.75 mmol) and amino acids (0.9 mmol) at room temperature. Then, the sealed tube was placed in an oil bath at room temperature. The oil
bath was subsequently heated to 120 ˚C. The reaction mixture was stirred at 120 ˚C (oil bath temperature) for 10 hours. After the reaction
was completed, the resulting mixture was extracted with EtOAc (3×10 mL), dried with Na2SO4. Then the solvent was removed under
reduced pressure and purified by silica gel column chromatography (Hex : EtOAc= 15:1-2:1) to afford the desired product as a yellow
solid or pale green oil.
3-isobutyl-1-phenylimidazo[1,5-a]pyridine (3a)11. Isolated yield: 92% (69 mg), pale green oil. 1H NMR (400 MHz, CDCl3) δ 7.86 (d, J
= 7.8 Hz, 2H), 7.78 – 7.76 (m, 2H), 7.44 (t, J = 7.4 Hz, 2H), 7.28 – 7.24 (m, 1H), 6.74 – 6.70 (m, 1H), 6.56 (t, J = 6.8 Hz, 1H), 2.94 (d, J =
7.2 Hz, 2H), 2.31 – 2.23 (m, 1H), 1.03 (d, J = 6.6 Hz, 6H). 13C NMR (100 MHz, CDCl3) δ 139.0, 135.3, 130.1, 128.7, 126.7, 126.4, 126.2,
121.1, 119.1, 118.7, 112.5, 28.7, 20.7, 14.1. HRMS calc. C17H19N2 (M+H+): 251.1548, Found: 251.1551.
3-isobutyl-1-(p-tolyl)imidazo[1,5-a]pyridine (3b). Isolated yield: 92% (73 mg), pale green oil. 1H NMR (400 MHz, CDCl3) δ 7.73 (t, J =
8.4 Hz, 4H), 7.26 (s, 1H), 7.24 (s, 1H), 6.66 (dd, J = 9.2, 6.4 Hz, 1H), 6.51 (t, J = 6.7 Hz, 1H), 2.90 (d, J = 7.3 Hz, 2H), 2.38 (s, 3H), 2.30
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– 2.21 (m,1H), 1.01 (d, J = 6.6 Hz, 6H). 13C NMR (100 MHz, CDCl3) δ 138.3, 135.8, 132.5, 130.3, 129.4, 126.6, 126.1, 121.1, 119.1,
118.2, 112.3, 35.6, 27.9, 22.7, 21.3. HRMS calc. C18H21N2 (M+H+): 265.1705, Found: 265.1704.
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3-isobutyl-1-(4-methoxyphenyl)imidazo[1,5-a]pyridine (3c). Isolated yield: 89% (75 mg), pale green oil. 1H NMR (400 MHz, CDCl3) δ
7.78 (d, J = 8.5 Hz, 2H), 7.71 (dd, J = 12.6, 8.3 Hz, 2H), 6.99 (d, J = 8.5 Hz, 2H), 6.72 – 6.62 (m, 1H), 6.53 (t, J = 6.7 Hz, 1H), 3.85 (s,
3H), 2.93 (d, J = 7.3 Hz, 2H), 2.33 – 2.20 (m, 1H), 1.02 (d, J = 6.6 Hz, 6H). 13C NMR (100 MHz, CDCl3) δ 158.3, 138.2, 130.2, 128.2,
127.9, 125.8, 121.0, 119.1, 118.0, 114.3, 112.3, 55.4, 35.6, 28.0, 22.7. HRMS calc. C18H21N2O (M+H+): 281.1654, Found: 281.1653.
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3-isobutyl-1-(4-(trifluoromethyl)phenyl)imidazo[1,5-a]pyridine (3d). Isolated yield: 87% (83 mg), pale green oil. H NMR (400 MHz,
CDCl3) δ 7.98 (d, J = 8.2 Hz, 2H), 7.78 (t, J = 8.8 Hz, 2H), 7.67 (d, J = 8.3 Hz, 2H), 6.80 (dd, J = 9.2, 6.4 Hz, 1H), 6.61 (t, J = 6.7 Hz, 1H),
2.93 (d, J = 7.3 Hz, 2H), 2.33 – 2.26 (m, 1H), 1.03 (d, J = 6.6 Hz, 6H). 13C NMR (100 MHz, CDCl3) δ 139.2, 138.9, 128.5, 127.6 (d, 2JCF
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31 Hz), 127.3, 126.3, 125.7 (q, 3JCF = 4 Hz), 124.6 (d, 1JCF = 270 Hz), 121.5, 119.9, 118.7, 112.7, 35.6, 27.9, 22.7. HRMS calc. C18H17F3N2
(M+H+): 319.1422, Found: 319.1424.
3-isobutyl-1-(o-tolyl)imidazo[1,5-a]pyridine (3e). Isolated yield: 74% (59 mg), pale green oil. 1H NMR (400 MHz, CDCl3) δ 7.75 (d, J =
7.2 Hz, 1H), 7.45 – 7.43 (m, 1H), 7.36 (d, J = 9.1 Hz, 1H), 7.30 (d, J = 4.2 Hz, 1H), 7.25 – 7.23 (m, 2H), 6.63 (t, J = 6.6 Hz, 1H), 6.54 (t, J
= 6.6 Hz, 1H), 2.92 (d, J = 7.2 Hz, 2H), 2.40 (s, 3H), 2.32 – 2.24 (m, 1H), 1.03 (d, J = 6.6 Hz, 6H). 13C NMR (100 MHz, CDCl3) δ 137.7,
137.4, 134.0, 130.8, 130.4, 127.3, 127.1, 125.6, 120.8, 119.0, 117.7, 112.3, 35.6, 27.7, 22.7, 20.6. HRMS calc. C18H21N2 (M+H+):
265.1705, Found: 265.1706.
3-isobutyl-1-(m-tolyl)imidazo[1,5-a]pyridine (3f). Isolated yield: 88% (70 mg), pale green oil. 1H NMR (400 MHz, CDCl3) δ 7.74 (t, J =
7.3 Hz, 2H), 7.70 (s, 1H), 7.63 (d, J = 7.7 Hz, 1H), 7.32 (t, J = 7.6 Hz, 1H), 7.08 (d, J = 7.5 Hz, 1H), 6.68 (dd, J = 9.1, 6.5 Hz, 1H), 6.53 (t,
J = 6.8 Hz, 1H), 2.91 (d, J = 7.3 Hz, 2H), 2.42 (s, 3H), 2.25 – 2.22 (m, 1H), 1.01 (d, J = 6.6 Hz, 6H). 13C NMR (100 MHz, CDCl3) δ 138.5,
138.4, 135.2, 130.4, 128.6, 127.5, 127.1, 126.4, 123.7, 121.2, 119.2, 118.5, 112.4, 35.6, 28.0, 22.7, 21.7. HRMS calc. C18H21N2 (M+H+):
265.1705, Found: 265.1704.
1-(3-chlorophenyl)-3-isobutylimidazo[1,5-a]pyridine (3g). Isolated yield: 86% (73 mg), pale green foam. 1H NMR (400 MHz, CDCl3) δ
7.86 (m, 1H), 7.75 (dd, J = 11.2, 7.2 Hz, 3H), 7.35 (t, J = 7.9 Hz, 1H), 7.22 (d, J = 7.9 Hz, 1H), 6.76 (dd, J = 9.2, 6.3 Hz, 1H), 6.58 (t, J =
6.8 Hz, 1H), 2.91 (d, J = 7.3 Hz, 2H), 2.27 (m, 1H), 1.03 (d, J = 6.6 Hz, 6H). 13C NMR (100 MHz, CDCl3) δ 138.9, 137.2, 134.7, 129.9,
128.7, 126.9, 126.4, 126.1, 124.5, 121.4, 119.4, 118.8, 112.6, 35.6, 27.9, 22.8. HRMS calc. C17H18N2Cl (M+H+): 285.1159, Found:
285.1158.
1-(3,5-dimethylphenyl)-3-isobutylimidazo[1,5-a]pyridine (3h). Isolated yield: 86% (72 mg), pale green oil. 1H NMR (400 MHz, CDCl3)
δ 7.74 (t, J = 9.4 Hz, 2H), 7.47 (s, 2H), 6.91 (s, 1H), 6.72 – 6.63 (m, 1H), 6.52 (t, J = 6.7 Hz, 1H), 2.91 (d, J = 7.3 Hz, 2H), 2.38 (s, 6H),
2.30 – 2.21 (m, 1H), 1.00 (d, J = 6.6 Hz, 6H). 13C NMR (100 MHz, CDCl3) δ 138.4, 138.2, 135.2, 130.5, 128.1, 126.4, 124.5, 121.1, 119.3,
118.3, 112.4, 35.6, 28.0, 22.7, 21.5. HRMS calc. C19H23N2 (M+H+): 279.1861, Found: 279.1860.
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1-(3,5-difluorophenyl)-3-isobutylimidazo[1,5-a]pyridine (3i). Isolated yield: 85% (73 mg), pale green oil. H NMR (400 MHz, CDCl3)
δ 7.78 (d, J = 4 Hz, 1H), 7.74 (d, J = 8 Hz, 1H), 7.41 – 7.38 (m, 2H), 6.83 – 6.79 (m, 1H), 6.70-6.64 (m, 1H), 6.61 (t, J = 4 Hz, 1H), 2.90
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(d, J = 7.3 Hz, 2H), 2.33 – 2.20 (m, 1H), 1.03 (d, J = 6.6 Hz, 6H). 13C NMR (100 MHz, CDCl3) δ 163.6 (d, J = 244 Hz), 163.5 (d, J = 244
Hz), 139.04, 138.7 (t, J = 10.4 Hz), 127.9 (t, J = 3.2 Hz), 127.2, 121.6, 120.0, 118.6, 112.7, 108.8 (d, J = 25 Hz), 108.8 (d, J = 11 Hz),
101.1 (t, J = 26 Hz), 35.6, 27.9, 22.8. HRMS calc. C17H17F2N2 (M+H+): 287.1360, Found: 287.1359.
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3-isobutyl-1-(naphthalen-1-yl)imidazo[1,5-a]pyridine (3j). Isolated yield: 82% (74 mg), pale green foam. 1H NMR (400 MHz, CDCl3) δ
8.29 (d, J = 8.1 Hz, 1H), 7.88 (d, J = 7.5 Hz, 1H), 7.83 (d, J = 8.2 Hz, 1H), 7.78 (d, J = 7.1 Hz, 1H), 7.66 (d, J = 7.0 Hz, 1H), 7.53 (t, J =
7.6 Hz, 1H), 7.50 – 7.42 (m, 2H), 7.39 (d, J = 9.2 Hz, 1H), 6.67 – 6.58 (m, 1H), 6.54 (t, J = 6.7 Hz, 1H), 2.97 (d, J = 7.3 Hz, 2H), 2.32 (td,
J = 13.7, 6.9 Hz, 1H), 1.06 (d, J = 6.6 Hz, 6H). 13C NMR (100 MHz, CDCl3) δ 138.3, 134.3, 132.2, 132.1, 129.7, 128.2, 127.9, 127.7,
127.6, 126.6, 126.0, 125.7, 125.4, 120.9, 119.0, 118.1, 112.5, 35.7, 27.8, 22.8. HRMS calc. C21H21N2 (M+H+): 301.1705, Found: 301.1707.
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1-isobutyl-3-phenylimidazo[1,5-a]quinoline (3k). Isolated yield: 81% (72 mg), pale green foam. 1H NMR (400 MHz, CDCl3) δ 8.12 (d,
J = 8.5 Hz, 1H), 7.84 (d, J = 7.9 Hz, 2H), 7.61 (dd, J = 13.0, 8.6 Hz, 2H), 7.52 (t, J = 7.9 Hz, 1H), 7.46 (t, J = 7.5 Hz, 2H), 7.38 (t, J = 7.5
Hz, 1H), 7.31 (t, J = 7.3 Hz, 1H), 6.97 (d, J = 9.5 Hz, 1H), 3.32 (d, J = 7.0 Hz, 2H), 2.45 (dt, J = 13.3, 6.7 Hz, 1H), 1.11 (d, J = 6.6 Hz,
6H). 13C NMR (100 MHz, CDCl3) δ 143.3, 135.0, 133.2, 132.3, 128.7, 128.5, 127.8, 127.4, 126.7, 126.3, 126.0, 124.8, 121.1, 117.6, 116.6,
41.1, 26.6, 22.7. HRMS calc. C21H21N2 (M+H+): 301.1705, Found: 301.1704.
3-methyl-1-phenylimidazo[1,5-a]pyridine (4a)11. Isolated yield: 73% (45 mg), pale green oil. 1H NMR (400 MHz, CDCl3) δ 7.86 (d, J =
7.9 Hz, 2H), 7.78 (d, J = 9.2 Hz, 1H), 7.67 (d, J = 7.1 Hz, 1H), 7.44 (t, J = 7.6 Hz, 2H), 7.26 (t, J = 7.3 Hz, 1H), 6.74 (dd, J = 9.1, 6.5 Hz,
1H), 6.59 (t, J = 6.7 Hz, 1H), 2.71 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 135.3, 135.0, 130.0, 128.8, 126.6, 126.5, 126.3, 121.1, 119.1,
118.7, 112.6, 12.6. HRMS calc. C14H13N2 (M+H+): 209.1079, Found: 209.1081.
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1-phenyl-3-propylimidazo[1,5-a]pyridine (4b). Isolated yield: 72% (51 mg), pale green oil. H NMR (400 MHz, CDCl3) δ 7.85 (d, J =
8.0 Hz, 2H), 7.78 – 7.71 (m, 2H), 7.43 (t, J = 7.4 Hz, 2H), 7.27-7.23 (m, 1H), 6.72 – 6.68 (m, 1H), 6.54 (t, J = 6.6 Hz, 1H), 2.99 (t, J = 7.6
Hz, 2H), 1.94 – 1.82 (m, 2H), 1.05 (t, J = 7.3 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 139.0, 135.3, 130.1, 128.7, 126.7, 126.5, 126.2,
121.1, 119.1, 118.7, 112.5, 28.7, 20.7, 14.1. HRMS calc. C16H17N2 (M+H+): 237.1392, Found: 237.1394.
3-butyl-1-phenylimidazo[1,5-a]pyridine (4c). Isolated yield: 66% (50 mg), pale green oil. 1H NMR (400 MHz, CDCl3) δ 7.90 – 7.82 (m,
2H), 7.75 (dd, J = 13.1, 8.2 Hz, 2H), 7.44 (t, J = 7.7 Hz, 2H), 7.30 – 7.20 (m, 1H), 6.71 (dd, J = 9.2, 6.4 Hz, 1H), 6.55 (t, J = 6.7 Hz, 1H),
3.06 – 3.01 (m, 2H), 1.88 – 1.80 (m, 2H), 1.53 – 1.44 (m, 2H), 0.98 (t, J = 7.4 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 139.2, 135.4, 130.1,
128.8, 126.7, 126.5, 126.2, 121.1, 119.1, 118.7, 112.5, 29.4, 26.6, 22.8, 14.0. HRMS calc. C17H19N2 (M+H+): 251.1548, Found: 251.1550.
3-(sec-butyl)-1-phenylimidazo[1,5-a]pyridine (4d). Isolated yield: 83% (62 mg), pale green oil. 1H NMR (400 MHz, CDCl3) δ 7.85 (d, J
= 7.8 Hz, 2H), 7.74 (t, J = 8.2 Hz, 2H), 7.42 (t, J = 7.5 Hz, 2H), 7.26 – 7.22 (m, 1H), 6.76 – 6.59 (m, 1H), 6.51 (t, J = 6.7 Hz, 1H), 3.11 (dd,
J = 13.8, 6.9 Hz, 1H), 2.02 (dt, J = 14.3, 7.2 Hz, 1H), 1.79 (dt, J = 14.0, 7.1 Hz, 1H), 1.45 (d, J = 6.9 Hz, 3H), 0.94 (t, J = 7.4 Hz, 3H). 13
C
NMR (100 MHz, CDCl3) δ 142.9, 135.5, 130.1, 128.7, 126.8, 126.4, 126.1, 121.0, 119.1, 118.6, 112.3, 33.1, 28.3, 18.3, 12.2. HRMS calc.
C17H19N2 (M+H+): 251.1548, Found: 251.1550.
1,3-diphenylimidazo[1,5-a]pyridine (6a)10,11,15. Isolated yield: 93% (75 mg), yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.28 – 8.15 (m,
1H), 7.94 (d, J = 8.2 Hz, 2H), 7.82 (dd, J = 9.1, 2.0 Hz, 3H), 7.52 (t, J = 7.5 Hz, 2H), 7.49 – 7.40 (m, 3H), 7.29 (t, J = 7.4 Hz, 1H), 6.83 –
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6.71 (m, 1H), 6.60 – 6.46 (m, 1H). 13C NMR (100 MHz, CDCl3) δ 138.2, 135.0, 132.0, 130.2, 129.1, 128.9, 128.8, 128.4, 127.8, 126.9,
126.6, 121.8, 119.8, 119.2, 113.3. MS (EI) m/z 270 (M+); mp 111-112oC.
3-phenyl-1-(p-tolyl)imidazo[1,5-a]pyridine (6b)10,11. Isolated yield: 92% (78 mg), yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.20 (d, J
= 7.2Hz, 1H), 7.84 – 7.80 (m, 5H), 7.54 – 7.50 (m, 2H), 7.46 – 7.42 (m, 1H), 7.28 – 7.25 (m, 2H), 6.77 – 6.73 (m, 1H), 6.56 – 6.52 (m,
1H), 2.40 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 137.9, 136.2, 132.1, 132.0, 130.2, 129.4, 129.0, 128.8, 128.4, 127.4, 126.7, 121.7, 119.4,
119.3, 113.2, 21.3. MS (EI) m/z 284 (M+); mp 133-134oC.
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1-(4-methoxyphenyl)-3-phenylimidazo[1,5-a]pyridine (6c)10,11. Isolated yield: 89% (80 mg), yellow solid. H NMR (300 MHz, CDCl3)
δ 8.22 – 8.20 (d, J = 7.2 Hz, 1H), 7.87 – 7.76 (m, 5H), 7.55 – 7.41 (m, 3H), 7.03 – 7.00 (d, J = 8.4Hz, 2H), 6.76 – 6.71 (m, 1H), 6.56 –
6.52 (m, 1H), 3.86 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 158.6, 137.8, 132.0, 130.2, 129.0, 128.7, 128.3, 128.1, 127.7, 127.1, 121.6,
119.2, 119.2, 114.2, 113.2, 55.4. MS (EI) m/z 300 (M+); mp 115-116oC.
3-phenyl-1-(4-(trifluoromethyl)phenyl)imidazo[1,5-a]pyridine (6d)9a,10,11. Isolated yield: 86% (87 mg), yellow solid. H NMR (300
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MHz, CDCl3) δ 8.24 (d, J = 7.5 Hz, 1H), 8.05 (d, J = 8.1Hz, 2H), 7.86 – 7.81 (m, 3H), 7.69 (d, J = 8.2 Hz, 2H), 7.57 – 7.44 (m, 3H), 6.89
– 6.84 (m, 1H), 6.60 (t, J = 6.6 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 138.8, 138.7, 131.4, 130.3, 130.0, 129.2, 128.5, 128.4, 128.2 (d, J
= 40 Hz), 126.6, 125.7 (q, J = 4 Hz), 124. 6 (d, J = 270 Hz), 122.2, 121.0, 118.8, 113.6. MS (EI) m/z 338 (M+); mp 184-185oC.
3-phenyl-1-(o-tolyl)imidazo[1,5-a]pyridine (6e)10,11. Isolated yield: 82% (70 mg), greenyellow solid. 1H NMR (400 MHz, CDCl3) δ 8.28
– 8.25 (m, 1H), 7.87 – 7.84 (m, 2H), 7.53 – 7.49 (m, 3H), 7.44 – 7.39 (m, 2H), 7.33 – 7.31 (m, 1H), 7.27 – 7.25 (m, 2H), 6.71 – 6.67 (m,
3H), 6.57-6.53 (m, 3H), 2.46 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 137.40, 137.39, 133.6, 132.8, 130.8, 130.4, 129.9, 128.6, 128.5,
128.1, 127.4, 125.6, 121.4, 119.1, 118.8, 113.2, 20.6. MS (EI) m/z 284 (M+); mp 118-119oC.
3-phenyl-1-(m-tolyl)imidazo[1,5-a]pyridine (6f)10,11. Isolated yield: 91% (77 mg), greenyellow solid. 1H NMR (300 MHz, CDCl3) δ 8.23
– 8.21 (d, J = 7.2 Hz, 1H), 7.85 – 7.80 (m, 4H), 7.72 – 7.70 (d, J = 8.1 Hz, 1H), 7.56 – 7.50 (m, 2H), 7.47 – 7.44 (m, 1H), 7.38 – 7.33 (t, J
= 15.3 Hz,1H), 7.13 – 7.10 (d, J = 7.5 Hz, 1H), 6.80 – 6.74 (m, 1H), 6.60 – 6.63 (m, 1H), 2.44 (s, 3H), 13C NMR (75 MHz, CDCl3) δ 138.4,
138.1, 134.8, 132.2, 130.2, 129.0, 128.8, 128.6, 128.4, 127.6, 127.4, 123.8, 121.7, 119.6, 119.3, 113.2, 21.6. MS (EI) m/z 284 (M+); mp
111-112oC.
1-(3-chlorophenyl)-3-phenylimidazo[1,5-a]pyridine (6g)10,11. Isolated yield: 86% (78 mg), greenyellow solid. 1H NMR (300 MHz,
CDCl3) δ 8.27 – 8.24 (d, J = 7.2 Hz, 1H), 7.96 (s, 1H), 7.85 – 7.82 (m, 4H), 7.57 – 7.36 (m, 4H), 7.26 (s, 1H), 6.88 – 6.83 (m, 1H), 6.64 –
6.59 (t, J = 13.5 Hz, 1H). 13C NMR (75 MHz, CDCl3) δ 138.4, 136.9, 134.7, 130.4, 129.9, 129.9, 129.1, 129.0, 128.4, 128.0, 126.6, 126.4,
124.6, 121.9, 120.4, 118.8, 113.4. HRMS calc. C19H14ClN2 (M+H+): 305.0846, Found: 305.0848; mp 131-132oC.
1-(3,5-dimethylphenyl)-3-phenylimidazo[1,5-a]pyridine (6h)10. Isolated yield: 90% (80 mg), greenyellow solid. H NMR (300 MHz,
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CDCl3) δ 8.24 – 8.21 (d, J = 7.2 Hz, 1H), 7.86 – 7.83 (m, 3H), 7.56 – 7.44 (m, 5H), 6.95 (s, 1H), 6.80 – 6.75 (m, 1H), 6.59 – 6.54 (m, 1H),
2.40 (s, 6H). 13C NMR (75 MHz, CDCl3) δ 138.2, 138.0, 134.8, 132.3, 130.2, 129.0, 128.8, 128.4, 127.6, 124.7, 121.7, 119.4, 119.4, 113.2,
21.5. MS (EI) m/z 298 (M+); mp 125-126oC.
1-(3,5-dimethoxyphenyl)-3-phenylimidazo[1,5-a]pyridine (6i)10. Isolated yield: 86% (85 mg), greenyellow solid. H NMR (400 MHz,
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CDCl3) δ 8.25 – 8.24 (d, J = 7.2 Hz, 1H), 7.88 – 7.85 (m, 3H), 7.57 – 7.53(m, 2H), 7.49 – 7.45 (t, J = 14.8 Hz, 1H), 7.13 – 7.12 (d, J = 2.4
Hz, 2H), 6.84 – 6.80 (m, 1H), 6.63 – 6.60 (t, J = 13.2 Hz, 1H), 6.46 – 6.45 (t, J = 4 Hz, 1H), 3.89 (s, 6H). 13C NMR (100 MHz, CDCl3) δ
161.1, 137.9, 136.7, 131.7, 130.0, 129.1, 128.9, 128.4, 127.9, 121.8, 120.0, 119.2, 113.4, 104.9, 99.2, 55.5. MS (EI) m/z 330 (M+); mp
178-179oC.
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1-(3,5-difluorophenyl)-3-phenylimidazo[1,5-a]pyridine (6j)10. Isolated yield: 83% (76 mg), greenyellow solid. H NMR (300 MHz,
CDCl3) δ 8.28 – 8.25 (d, J = 7.2 Hz, 1H), 7.84 – 7.82 (m, 3H), 7.58 – 7.50 (m, 5H), 6.93 – 6.88 (m, 1H), 6.75 – 6.62 (m, 2H). 13C NMR
(75 MHz, CDCl3) δ 163.6 (d, J = 245 Hz), 163.5 (d, J = 245 Hz), 138.5, 138.3, 129.8, 129.6, 129.2, 129.1, 128.4, 128.3, 122.2, 121.0,
118.6, 113.5, 109.1, 109.0, 108.9, 108.8, 101.4 (t, J = 25.5 Hz). MS (EI) m/z 306 (M+); mp 164-165oC.
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1-(3,5-dichlorophenyl)-3-phenylimidazo[1,5-a]pyridine (6k)10. Isolated yield: 83% (84 mg), greenyellow solid. H NMR (300 MHz,
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CDCl3) δ 8.28 – 8.25 (d, J = 7.2 Hz, 1H), 7.85 – 7.81 (m, 4H), 7.58 – 7.48 (m, 4H), 6.93 – 6.88 (m, 1H), 6.67 – 6.62 (t, J = 13.8 Hz, 1H).
13C NMR (75 MHz, CDCl3) δ 138.7, 138.0, 135.3, 129.8, 129.2, 129.1, 129.0, 128.4, 126.0, 124.6, 122.2, 121.1, 118.6, 113.5. MS (EI) m/z
339 (M+); mp 188-189oC.
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1-(3,5-bis(trifluoromethyl)phenyl)-3-phenylimidazo[1,5-a]pyridine (6l)10. Isolated yield: 81% (98 mg), greenyellow solid. H NMR
(300 MHz, CDCl3) δ 8.40 (s, 2H), 8.31 – 8.28 (d, J = 6.9 Hz, 1H), 7.85 – 7.83 (m, 3H), 7.75 (s, 1H), 7.60 – 7.48 (m, 3H), 7.00 – 6.94 (m,
1H), 6.71 – 6.66 (t, J = 13.5 Hz, 1H). 13C NMR (75 MHz, CDCl3) δ 139.1, 137.3, 132.0 (q, J = 33 Hz), 129.6, 129.4, 129.2, 128.7, 128.5,
126.1, 123.6 (d, J = 277 Hz), 122.4, 121.8, 119.4 (q, J = 3.8 Hz), 118.2, 113.7. MS (EI) m/z 406 (M+); mp 134-135oC.
1-(naphthalen-1-yl)-3-phenylimidazo[1,5-a]pyridine (6m)10. Isolated yield: 89% (85 mg), greenyellow solid. 1H NMR (300 MHz,
CDCl3) δ 8.39 – 8.36 (m, 1H), 8.31 – 8.29 (d, J = 7.2 Hz, 1H), 7.92 – 7.85 (m, 4H), 7.75 – 7.73 (m, 1H), 7.58 – 7.41 (m, 7H), 6.71 – 6.66
(m, 1H), 6.59 – 6.54 (m, 1H). 13C NMR (75 MHz, CDCl3) δ 138.0, 134.2, 132.1, 131.8, 131.7, 130.3, 129.3, 129.0, 128.7, 128.2, 127.7,
128.6, 126.1, 125.8, 125.4, 121.6, 119.2, 119.2, 113.4. MS (EI) m/z 320 (M+); mp 118-119oC.
1,3-diphenylimidazo[1,5-a]quinoline (6n)10. Isolated yield: 84% (81 mg), greenyellow solid. 1H NMR (400 MHz, CDCl3) δ 7.91 (d, J =
7.4 Hz, 2H), 7.72 – 7.64 (m, 3H), 7.61 (d, J = 7.6 Hz, 1H), 7.56 – 7.51 (m, 3H), 7.47 (t, J = 7.9 Hz, 3H), 7.36 – 7.28 (m, 2H), 7.16 (dd, J =
11.6, 4.2 Hz, 1H), 7.07 (d, J = 9.5 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 142.1, 134.2, 133.7, 133.4, 132.5, 129.9, 129.7, 129.1, 128.8,
128.6, 127.7, 127.6, 127.2, 126.5, 125.8, 125.4, 122.4, 117.8, 117.5. MS (EI) m/z 320 (M+); mp 136-137oC.
3-(4-fluorophenyl)-1-phenylimidazo[1,5-a]pyridine (6o)10,11. Isolated yield: 84% (73 mg), greenyellow solid. 1H NMR (400 MHz,
CDCl3) δ 8.14 (d, J = 7.2 Hz, 1H), 7.92 (d, J = 7.5 Hz, 2H), 7.87 – 7.74 (m, 3H), 7.46 (t, J = 7.6 Hz, 2H), 7.30 (t, J = 7.3 Hz, 1H), 7.26 –
7.20 (m, 2H), 6.78 (dd, J = 9.0, 6.5 Hz, 1H), 6.57 (t, J = 6.7 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 163.0 (d, J = 250 Hz), 137.3, 135.0,
132.1, 130.4 (d, J = 8.3 Hz), 128.9, 127.8, 126.9, 126.7, 126.50 (d, J = 3.2 Hz), 121.6, 119.8, 119.3, 116.2 (d, J = 22 Hz), 113.5. HRMS
calc. C19H14FN2 (M+): 289.1141, Found: 289.1139; mp 168-169 oC.
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3-(4-chlorophenyl)-1-phenylimidazo[1,5-a]pyridine (6p)10,11,16. Isolated yield: 81% (74 mg), greenyellow solid. H NMR (300 MHz,
CDCl3) δ 8.21 – 8.18 (d, J = 6.6 Hz, 1H), 7.94 – 7.79 (m, 5H), 7.53 – 7.45 (m, 4H), 7.33 – 7.26 (m, 1H), 6.85 – 6.79 (m, 1H), 6.64 – 6.60
(t, J = 13.2 Hz, 1H). 13C NMR (75 MHz, CDCl3) δ 136.9, 134.7, 134.7, 132.3, 129.5, 129.3, 128.8, 128.6, 127.9, 126.8, 126.7, 121.5,
119.9, 119.3, 113.6. MS (EI) m/z 304 (M+); mp 172-173oC.
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3-(3-fluorophenyl)-1-phenylimidazo[1,5-a]pyridine (6q). Isolated yield: 81% (70 mg), greenyellow solid. H NMR (400 MHz, CDCl3)
δ 8.24 (d, J = 7.1 Hz, 1H), 7.92 (d, J = 7.4 Hz, 2H), 7.85 (d, J = 9.2 Hz, 1H), 7.63 (d, J = 7.7 Hz, 1H), 7.57 (d, J = 9.5 Hz, 1H), 7.48 (dt, J
= 13.5, 7.9 Hz, 3H), 7.31 (t, J = 7.3 Hz, 1H), 7.20 – 7.08 (m, 1H), 6.87 – 6.73 (m, 1H), 6.61 (t, J = 6.7 Hz, 1H). 13C NMR (100 MHz,
CDCl3) δ 163.2 (d, J = 250 Hz), 136.8 (d, J = 3 Hz), 134.9, 132.5, 132.4 (d, J = 8 Hz), 130.8 (d, J = 8 Hz), 128.9, 128.1, 126.9, 126.8,
123.8 (d, J = 3 Hz), 121.7, 120.1, 119.4, 115.8 (d, J = 21 Hz), 115.4 (d, J = 23 Hz), 113.8. HRMS calc. C19H14FN2 (M+H+): 289.1141,
Found: 289.1140; mp 150-151oC.
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The 1H and 13CNMR spectra for all products. This material is available free of charge via the Internet at http://pubs.acs.org.
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Note: The authors declare no competing financial interest.
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Acknowledgments
We are grateful to the Natural Science Foundation of China (U1504208, 21302105) and the financial support from He’nan Provincial
Department of Science and Technology (152300410117).
References
1. For selected recent reviews, see: (a) Gooßen, L. J.; Rodríguez, N.; Gooßen, K. Angew. Chem. Int. Ed. 2008, 47, 3100-3120. (b) Rodríguez, N.; Goossen,
L. J. Chem. Soc. Rev. 2011, 40, 5030-5048. (c) Weaver, J. D.; Recio, A.; Grenning, A. J.; Tunge, J. A. Chem. Rev. 2011, 111, 1846-1913. (d) Shang, R.;
Liu, L. Sci. China Chem. 2011, 54, 1670-1687. (e) Cornella, J.; Larrosa, I. Synthesis. 2012, 44, 653-676. (f) Park, K.; Lee, S. RSC Adv. 2013, 3, 14165-
14182. (g) Shen, C.; Zhang, P.; Sun, Q.; Bai, S.; Hor, T. S. A.; Liu, X. Chem. Soc. Rev. 2015, 44, 291-314.
2. For selected examples on C-C bonds formation, see: (a) Bi, H.; Zhao, L.; Liang, Y.-M.; Li, C.-J. Angew. Chem. Int. Ed. 2009, 48, 792-795; (b) Zhang,
C.; Seidel, D. J. Am. Chem. Soc. 2010, 132, 1798–1799; (c) Liu, H.; Duan, T.; Zhang, Z.; Xie, C.; Ma, C. Org. Lett. 2015, 17, 2932-2935.
3. For selected examples on C-N bonds formation, see: (a) Yan, Y. Z.; Wang, Z. Y. Chem. Commun. 2011, 47, 9513-9515; (b) Xu, W.; Kloeckner, U.;
Nachtsheim, B. J. J. Org. Chem. 2013, 78, 6065-6074; (c) Zhao, D.; Wang, T.; Shen, Q.; Li, J.-X. Chem. Commun. 2014, 50, 4302-4304; (d) Xiang, J.-
C.; Wang, M.; Cheng, Y.; Wu, A.-X. Org. Lett. 2016, 18, 24-27.
4. For selected examples on C-O bonds formation, see: (a) Francisco, C. G.; González, C. C.; Suárez, E. Terrnhedron Lett. 1997, 38, 4141-4144; (b) Boto,
A.; Hernández, R.; Suárez, E. J. Org. Chem. 2000, 65, 4930-4937; (c) Xu, K.; Wang, Z. Q.; Zhang, J. J.; Yu, L. T.; Tan, J. Org. Lett. 2015, 17, 4476-
4478.
5. (a) Kim, D. Bioorg. Med. Chem. Lett. 2005, 15, 2129-2134; (b) Kakehi, S. H.; Okumura, Y.; Itoh, K.; Kobayashi, K.; Aikawa, Y.; Misawa, K. Chem.
Pharm. Bull. 2010, 58, 1502-1510.
6. (a) Bower, J. D.; Ramage, C. R. J. Chem. Soc. 1955, 2834-2837; (b) Pelletier, G.; Charette, A. B. Org. Lett. 2013, 15, 2290-2293 and references cited
therein.
7. For selected examples, see: (a) Shibahara, F.; Kitagawa, A.; Yamaguchi, E.; Murai, T. Org. Lett. 2006, 8, 5621-5624 and references cited therein; (b) Li,
M. Y.; Xie, Y.; Ye, Y.; Zou, Y.; Jiang, H. F.; Zeng, W. Org. Lett. 2014, 16, 6232-6235 and references cited therein.
8. Wang et al. has reported an iodine-mediated decarboxylation reaction of amino acids with quinoline-2-carbaldehyde for the synthesis of imidazo[1,5-
a]quinoline, however, the substrate scope was limited to aldehyde. 2-benzoylpyridines or 2-benzoylquinolines didn’t work under this oxidative reaction
conditions, see: Wang, Q.; Zhang, S.; Guo, F. F.; Zhang, B. Q.; Hu, P.; Wang, Z. Y. J. Org. Chem. 2012, 77, 11161-11166.
9. Successful examples on the synthesis of 1,3-disubstituted imidazo[1,5-a]pyridines, see: (a) Shibahara, F.; Sugiura, R.; Yamaguchi, E.; Kitagawa, A.;
Murai, T. J. Org. Chem. 2009, 74, 3566-3568; (b) Shi, Y.; Gulevich, A. V.; Gevorgyan, V. Angew. Chem., Int. Ed. 2014, 53, 14191-14195; (c) Xie, Z.;
Peng, J.; Zhu, Q. Org. Chem. Front. 2016, 3, 82-86. An example for the synthesis of 1,3-disubstituted imidazo[1,5-a]pyridines via the decarboxylation
reaction of amino acids, see: (d) Yan, Y. Z.; Zhang, Y. H.; Zha, Z. G.; Wang, Z. Y.; Org. Lett. 2013, 15, 2274-2277.
10. Wang, H. Q.; Xu, W. T.; Wang, Z. Q.; Yu, L. T.; Xu, K. J. Org. Chem. 2015, 80, 2431-2435.
11. During the preparation of this manuscript, Adimurthy and coworkers reported an elegant method for the synthesis of 1,3-disubstituted imidazo[1,5-
a]pyridines; see: Joshi, A.; Mohan, D. C.; Adimurthy, S. Org. Lett. 2016, 18, 464-467. In this work, three typical 3-alkyl-1-arylimidazo[1,5-a]pyridines
were synthesized in 51-65% yields.
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12. For selected recent reports on copper catalyzed decarboxylation reaction, see: (a) Shang, R.; Fu, Y.; Wang, Y.; Xu, Q.; Yu, H.-Z.; Liu, L. Angew. Chem.
Int. Ed. 2009, 48, 9350-9354; (b) Ranjit, S.; Duan, Z.; Zhang, P.; Liu, X. Org. Lett. 2010, 12, 4134-4137; (c) Zhang, Y.; Patel, S.; Mainolfi, N. Chem.
Sci. 2012, 3, 3196-3199; (d) Feng, Y.-S.; Xu, Z.-Q.; Mao, L.; Zhang, F.-F.; Xu, H.-J. Org. Lett. 2013, 15, 1472-1475; (e) Feng, Q.; Song, Q. J. Org.
Chem. 2014, 79, 1867-1871.
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13. For selected examples on azomethine ylide-type intermediate, see: (a) Coldham, I.; Hufton, R. Chem. Rev. 2005, 105, 2765-2809; (b) Pandey, G.;
Banerjee, P.; Gadre, S. R. Chem. Soc. Rev. 2006, 106, 4484-4517; (c) Zheng, L.; Yang, F.; Dang, Q.; Bai, X. Org. Lett. 2008, 10, 889-892; (d) Bi, H.;
Chen, W.-W.; Liang, Y.-M.; Li, C.-J. Org. Lett. 2009, 11, 3246-3249; (e) Seidel, D. Acc. Chem. Res. 2015, 48, 317–328 and references cited therein.
14. For selected examples on intramolecular sp3 C-H amination, see: Jeffrey, J. L.; Sarpong, R. Chem. Sci. 2013, 4, 4092-4106 and references cited therein.
15. Shibahara, F.; Yamaguchi, E.; Kitagawa, A.; Imai, A.; Murai, T. Tetrahedron 2009, 65, 5062-5073.
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16. Kovtun, P. Y.; Prostota, A. Y. Chem. Heterocycl. Compd. 2000, 36, 557-559.
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