Copper-catalyzed oxidative amination of sp3 C-h bonds under air: Synthesis of 1,3-diarylated imidazo[1,5-a ]pyridines

Article abstract of DOI:10.1021/jo5027723

A copper(II)-catalyzed tandem reaction between pyridine ketone and benzylamine was developed by using clean O₂ as an oxidant. This transformation proceeded via an efficient condensation-amination-oxidative dehydrogenation process, affording 1,3-diarylated imidazo[1,5-a]pyridines in excellent yields.

Full text of DOI:10.1021/jo5027723

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Note
Copper-Catalyzed Oxidative Amination of sp3 C-H Bonds
under Air:Synthesis of 1,3-diarylated Imidazo[1,5-a]pyridines
Huiqiao Wang, Wentao Xu, Zhiqiang Wang, Lintao Yu, and Kun Xu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo5027723 • Publication Date (Web): 28 Jan 2015
Downloaded from http://pubs.acs.org on January 29, 2015
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Copper-Catalyzed Oxidative Amination of sp3 C−H Bonds under Air: Synthesis of 1,3-diarylated
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Imidazo[1,5-a]pyridines
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Huiqiao Wang, Wentao Xu, Zhiqiang Wang, Lintao Yu 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
Abstract: A copper (II)-catalyzed tandem reaction between pyridine ketone and benzylamine was developed by using clean O2 as an oxidant.
This transformation proceeded via an efficient condensation-amination-oxidative dehydrogenation process, affording 1,3-diarylated
imidazo[1,5-a]pyridines in excellent yields.
Imidazo[1,5-a]pyridines exist widely in both natural products and synthetic compounds of high utility in pharmaceutical and materials
chemistry.1 However, only a few synthetic routes mainly relied on traditional Vilsmeier-type cyclizations2 and other alternative methods3
are available so far. Therefore, more straightforward method for the preparation of imidazo[1,5-a] pyridines from easily available
substrates is highly desirable.
Transition-metal-catalyzed direct aminations of C-H bonds have emerged as important approaches for C-N bond formations. As a result,
recent years have witnessed a rapid growth in the development of amination procedures. While synthetic methods enabling sp2 C−N bond
formation have been well-established4, facile intramolecular amination at sp3 C−H bonds under aerobic oxidative conditions still remains a
great challenge in synthetic chemistry.5, 6 As a continuous study on constructing C-C/C-N bonds more environmentally friendly7, we
hypothesized that 1,3-diarylated imidazo[1,5-a]pyridine could be synthesized from pyridine ketone and benzylamine via a sp3 C-H
amination process under aerobic conditions (Scheme 1). We herein report our efforts to develop a new tandem reaction for the synthesis of
1,3-diarylated imidazo[1,5-a]pyridine by using clean O2 as an oxidant.8
Scheme 1. Initial hypothesis pathway for sp3 C-H amination
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In order to explore aerobic oxidative amination of sp3 C−H bonds, 2-benzoylpyridine 1a was chosen as a model substrate to react with
benzylamine 2a under air (Table 1). First, the reactions were performed with different transition metal catalysts under air atmosphere, it
was found that Cu(OAc)2 was the most efficient catalyst for this reaction, which gave the desired product 3a in 87% yield (Table 1, entry
2); while other Lewis acids, such as CuI, Cu(OTf)2 and FeCl3 gave the desired product in lower yields (Table 1, entries 1, 3-4). However,
the reaction didn’t work when Zn(OAc)2 was employed as a catalyst (Table 1, entry 5). In the absence of the metal catalyst, the reaction
didn’t work at all (Table 1, entry 6), which indicated that copper salt played an essential role in this transformation. Subsequently, the
influence of oxidants on this reaction was investigated. The results showed that air would be the best choice with the respect of chemical
yields (Table 1, entries 2 vs 7-9). Further assessment of the reaction conditions indicated that DMF was the optimal solvent; while other
solvents gave lower yields (Table 1, entries 2 vs 10-14). The temperature had an obvious effect on the reaction, for example, increasing the
reaction temperature to 110 oC, the yield was improved to 93% (Table 1, entry 16).
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Table 1 Optimization of the reaction conditionsa
a Reaction conditions: 1a (1.0 equiv, 0.2 mmol), 2a (3.0 equiv), catalyst (0.15 equiv), oxidant (1 atm for air, 2 equiv for peroxide) in solvent (1 mL), 8h. b
Isolated yield.
With the optimized conditions in hand (Table 1, entry 16), we next investigated the substrate scope of pyridine ketone derivatives (Table
2). Common substituents including electron-donating and electron-withdrawing groups were all tolerated under the standard conditions,
giving the corresponding products 3b-3m in good to excellent yields. The electronic effects of R1 group had little influence on the yield;
however, the steric hindrance of R1 group had an obvious effect on the yield. The ortho-substituted methyl group on R1 decreased the yield
to 82% (entry 1), while the para-substitution and meta-substitution had little effect on the yield (entries 2-12). In addition, when 2-benzoyl
quinoline 1n was employed as the substrate, the corresponding product 3n could be obtained in 65% yield (entry 13).
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Table 2 The substrate scope of 2-benzoylpyridine derivatives a
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a Reaction conditions: 1 (1.0 equiv, 0.2 mmol), 2a (3.0 equiv), Cu(OAc)2 H2O (0.15 equiv) in solvent (1 mL), 8h. b Isolated yield.
Subsequently, a series of benzylamine derivatives 2o-2w were employed to react with 2-benzoylpyridine 1a under the optimized
conditions (Table 3). In general, a range of benzylamine derivatives with both electron-donating and electron-withdrawing groups worked
well in this reaction, giving the corresponding products 3o-3u in excellent yields (entries 1-7). The ring-fused benzylamine also gave the
corresponding product 3v in excellent yield (entry 8). Moreover, heterocyclic benzylamines could undergo the tandem reaction smoothly
to give the corresponding product 3w and 3x in 63% and 31% yields respectively (entries 9 and 10). However, for other long chain
aliphatic amines, no corresponding products were obtained.
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Table 3 The substrate scope of benzylamine derivativesa
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a Reaction conditions: 1a (1.0 equiv, 0.2 mmol), 2 (3.0 equiv), Cu(OAc)2 H2O (0.15 equiv) in solvent (1 mL), 8h. b Isolated yield.
On the basis of the above results and previous reports, a possible mechanism is proposed and shown in Scheme 2. First, the
condensation reaction between 2-benzoylpyridine 1a and benzylamine 2a generates intermediate A. Subsequently, an oxidative
dehydrogenation in A gives intermediate B9,10, which has a resonance structure of intermediate C. Then, the intramolecular amination in
intermediate C leads to the formation of cyclised intermediate D11, which can undergo sequential oxidative dehydrogenation and
rearrangement to yield imidazo[1,5-a]pyridine 3a.
Scheme 2. A tentative mechanism for the formation of 3a.
In summary, we have developed an efficient oxidative amination of sp3 C-H bonds under air. This tandem reaction is operationally simple,
and a wide range of substituents are tolerated well to give 1,3-diarylated imidazo[1,5-a]pyridines in good to excellent yields. This protocol
can serve as a new tool for the synthesis of 1,3-diarylated imidazo[1,5-a]pyridines.
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Experimental Section
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General methods. NMR spectra were recorded on 300MHz or 400 MHz NMR spectrometer with CDCl3 as the solvent and
tetramethylsilane (TMS) as the internal standard. Chemical shifts were reported in parts per million (ppm, δ scale) downfield from TMS at
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0.00 ppm and referenced to the CDCl3 at 7.26 ppm (for H NMR) or 77.16 ppm (for 13C NMR). HRMS was obtained by Electron
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Ionization (EI) or Electrospray Ionization (ESI, only for product 3x) 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 typical Grignard reactions according to the
literatures.12-16 The benzylamine derivatives were commercially available and were used without further purification. DMF was distilled
over calcium hydride under reduced pressure.
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General procedure for the preparation of pyridine ketones. A solution of the bromobenzene (10.0 mmol, 1.00 equiv) in 15 mL of dry
THF was treated with magnesium (12 mmol, 1.2 equiv). After the formation of the Grignard reagent, the solution was added to a solution
of the carbonitrile (8 mmol, 0.8 equiv) in THF (10 mL) at 0 °C. After the reaction was completed, the reaction was quenched by addition
of a solution of saturated NH4Cl. The organic layer was separated and extracted twice with CH2Cl2. After evaporation, the organic layer
was redissolved in Et2O (30 mL) and 6 M HCl (6 mL) was added. After 30 min, the organic layer was separated, and the aqueous layer
was basified with saturated NaHCO3 and then extracted three times with CH2Cl2. The combined organic layers were dried over Na2SO4
and evaporated in vacuo. The residue was purified by column chromatography with petroleum ether and ethyl acetate (6:1) to afford 1a as
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a white solid (79% yield). H NMR (400 MHz, CDCl3) δ 8.70-8.67 (m, 1H), 8.10-8.06 (m, 1H), 7.89-7.86 (m, 1H), 7.47−7.38 (m, 3H),
7.29−7.23 (m, 2H), 2.38 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 197.5, 155.2, 149.4, 137.9, 137.7, 137.5, 131.5, 131.4, 130.9, 126.7,
125.1, 124.2, 20.6.
Other pyridine ketones 1b-1w were prepared with the similar procedures, and characterized by GC-MS.
General procedure for the synthesis of 1, 3-diarylated imidazo[1,5-a]pyridines (Tables 2 and 3). To a solution of phenyl-(pyridin-2-
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yl)-methanone 1a (0.2 mmol) in distilled DMF (1.0 mL) was added Cu(OAc)2 H2O (0.03 mmol) and benzylamine 2a (0.6 mmol) at room
temperature. Then, the reaction mixture was stirred at 110˚C for 8 hours under air. 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= 4:1-2:1) to afford the desired product as a yellow solid.
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1,3-diphenylimidazo[1,5-a]pyridine (3a)17. Isolated yield: 93% (50 mg), yellow solid. H NMR (400 MHz, CDCl3)  8.22-8.20 (d, J =
7.2 Hz, 1H), 7.95 (s, 1H), 7.93 (s, 1H), 7.83-7.81 (m, 3H), 7.54-7.41 (m, 5H), 7.31-7.27 (t, J = 7.2 Hz, 1H), 6.78-6.74 (m, 1H), 6.56-6.52
(t, J = 7.2 Hz, 1H). 13C NMR (101 MHz, CDCl3)  136.1, 135.0, 132.0, 130.2, 129.0, 128.8, 128.7, 128.3, 127.7, 126.8, 126.5, 121.7,
119.7, 119.1, 113.2. MS (EI) m/z 270 (M+); IR(KBr) 697, 841, 1518, 1598, 2921 cm-1; mp110-111oC.
3-phenyl-1-o-tolylimidazo[1,5-a]pyridine (3b). Isolated yield: 82% (47 mg), yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.27 (d, J = 7.3
Hz, 1H), 7.87–7.85 (m, 2H), 7.55–7.48 (m, 3H), 7.44-7.42 (m, 2H), 7.34-7.32 (m, 1H), 7.29–7.24 (m, 2H), 6.72-6.68 (m, 1H), 6.63–6.45
(m, 1H), 2.46 (s, 1H). 13C NMR (101 MHz, CDCl3) δ 137.5, 133.7, 132.9, 130.9, 130.5, 129.1, 128.7, 128.6, 128.2, 127.6, 125.7, 121.6,
119.3, 119.0, 113.3, 20.7. HRMS calc. C20H16N2 (M+): 284.1313, Found: 284.1315. IR(KBr) 694, 822, 1500, 1601, 2915cm-1; mp 121-
122oC.
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3-phenyl-1-m-tolylimidazo[1,5-a]pyridine (3c). Isolated yield: 90% (51 mg), greenyellow solid. 1H NMR (400 MHz, CDCl3) δ 8.22 (d, J
= 7.2 Hz, 1H), 7.85-7.80 (m, 4H), 7.72 (d, J = 7.7 Hz, 1H), 7.54 (t, J = 7.6 Hz, 2H), 7.45 (t, J = 7.3 Hz, 1H), 7.37 (t, J = 7.6 Hz, 1H), 7.13
(d, J = 7.4 Hz, 1H), 6.78 (dd, J = 9.0, 6.5 Hz, 1H), 6.56 (t, J = 6.7 Hz, 1H), 2.45 (s, 1H). 13C NMR (101 MHz, CDCl3) δ 138.5, 138.1,
134.9, 132.2, 130.2, 129.1, 128.9, 128.7, 128.4, 127.73, 127.70, 127.5, 123.9, 121.8, 119.7, 119.3, 113.3, 21.7. HRMS calc. C20H16N2
(M+): 284.1313, Found: 284.1318. IR(KBr) 698, 822, 1602, 2924cm-1; mp111-112oC.
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3-phenyl-1-p-tolylimidazo[1,5-a]pyridine (3d)17. Isolated yield: 96% (55 mg), yellow solid. H NMR (400 MHz, CDCl3) δ 8.20 (d, J =
7.3 Hz, 1H), 7.83-7.79 (m, 5H), 7.55-7.50 (m, 2H), 7.45-7.41 (m, 1H), 7.27 (d, J = 8 Hz, 2H), 6.73 (dd, J = 9.2, 6.3 Hz, 1H), 6.54-6.51 (m,
1H), 2.40 (s, 1H). 13C NMR (101 MHz, CDCl3) δ 138.0, 136.3, 132.23, 132.16, 130.3, 129.5, 129.1, 128.9, 128.4, 127.5, 126.8, 121.8,
119.5, 119.3, 113.3, 21.4. MS (EI) m/z 284 (M+); IR(KBr) 696, 821, 1249, 1361, 1520, 1602, 2917cm-1; mp 131-132oC.
1-(4-methoxyphenyl)-3-phenylimidazo[1,5-a]pyridine (3e)17,. Isolated yield: 95% (57 mg), yellow solid. 1H NMR (400 MHz, CDCl3) δ
8.21 (d, J = 7.3 Hz, 1H), 7.87–7.82 (m, 4H), 7.78–7.76 (m, 1H), 7.55–7.51 (m, 2H), 7.44–7.42 (m, 1H), 7.04–7.00 (m, 2H), 6.73 (ddd, J =
9.2, 6.3, 0.8 Hz, 1H), 6.60–6.46 (m, 1H), 3.86 (s, 1H). 13C NMR (101 MHz, CDCl3) δ 158.7, 137.9, 132.1, 130.3, 129.1, 128.8, 128.4,
128.2, 127.8, 127.2, 121.7, 119.3, 114.3, 113.3, 55.5. MS (EI) m/z 300 (M+); IR(KBr) 694, 841, 1246, 1502, 2924cm-1; mp 112-113oC.
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1-(3,5-dimethylphenyl)-3-phenylimidazo[1,5-a]pyridine (3f). Isolated yield: 97% (58 mg), yellow solid. H NMR (400 MHz, CDCl3) δ
8.20 (d, J = 7.2 Hz, 1H), 7.84-7.81 (m, 3H), 7.55-7.50 (m, 4H), 7.43 (t, J = 7.4 Hz, 1H), 6.95 (s, 1H), 6.76 (dd, J = 9.2, 6.4 Hz, 1H), 6.54
(t, J = 6.8 Hz, 1H), 2.39 (s, 1H). 13C NMR (101 MHz, CDCl3) δ 138.3, 138.0, 134.7, 132.3, 130.2, 129.1, 128.9, 128.5, 128.5, 127.7,
124.8, 121.8, 119.6, 119.4, 113.4, 21.6. HRMS calc. C21H18N2 (M+): 298.1470, Found: 298.1472. IR(KBr) 696, 824, 1602, 2929cm-1; mp
123-124oC.
1-(3,5-dimethoxyphenyl)-3-phenylimidazo[1,5-a]pyridine (3g). Isolated yield: 90% (59 mg), yellow solid. 1H NMR (400 MHz, CDCl3)
 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)  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. HRMS calc. C21H18N2O2 (M+): 330.1368, Found:
330.1371. IR(KBr) 698, 704, 829, 1156, 1204, 1601, 2933cm-1; mp179-180oC.
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1-(naphthalen-1-yl)-3-phenylimidazo[1,5-a]pyridine (3h). Isolated yield: 85% (54 mg), yellow solid. H NMR (400 MHz, CDCl3) δ
8.41–8.36 (m, 1H), 8.34 (dt, J = 7.2, 1.0 Hz, 1H), 7.97–7.87 (m, 4H), 7.76 (dd, J = 7.1, 1.2 Hz, 1H), 7.61–7.54 (m, 3H), 7.54–7.43 (m,
4H), 6.73 (ddd, J = 9.2, 6.3, 0.9 Hz, 1H), 6.66–6.54 (m, 1H). 13C NMR (101 MHz, CDCl3) δ 138.1, 134.3, 132.2, 131.9, 131.7, 130.4,
129.3 (d, J = 28.4 Hz), 128.9, 128.4, 128.0, 127.9, 126.6, 126.2, 125.9, 125.5, 121.7, 119.4, 113.5. HRMS calc. C23H16N2 (M+): 320.1313,
Found: 320.1317. IR(KBr) 698, 769, 1506, 2926 cm-1; mp119-121oC.
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1-(3-chlorophenyl)-3-phenylimidazo[1,5-a]pyridine (3i). Isolated yield: 94% (57 mg), yellow solid. H NMR (400 MHz, CDCl3) δ
8.27–8.18 (m, 1H), 7.97–7.91 (m, 1H), 7.86–7.77 (m, 4H), 7.58–7.50 (m, 2H), 7.49–7.42 (m, 1H), 7.39–7.33 (m, 1H), 7.27–7.21 (m, 1H),
6.82 (ddd, J = 9.3, 6.4, 0.9 Hz, 1H), 6.63–6.53 (m, 1H). 13C NMR (101 MHz, CDCl3) δ 138.5, 136.9, 134.8, 130.5, 130.03, 129.97, 129.2,
129.1, 128.4, 128.1, 126.7, 126.5, 124.7, 122.1, 120.6, 118.9, 113.5. HRMS calc. C19H13ClN2 (M+): 304.0767, Found: 304.0771. IR(KBr)
691, 792, 1316, 1590, 2921cm-1; mp 136-137oC.
3-phenyl-1-(4-(trifluoromethyl)phenyl)imidazo[1,5-a]pyridine (3j)3c. Isolated yield: 95% (64 mg), yellow solid. H NMR (400 MHz,
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CDCl3) δ 8.26 (d, J = 7.2 Hz, 1H), 8.07 (d, J = 8.1 Hz, 2H), 7.84 (dd, J = 8.1, 6.7 Hz, 3H), 7.71 (d, J = 8.2 Hz, 2H), 7.56 (t, J = 7.4 Hz,
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2H), 7.48 (ddd, J = 7.4, 3.8, 1.2 Hz, 1H), 6.88 (dd, J = 9.2, 6.4 Hz, 1H), 6.63 (t, J = 6.8 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 138.8,
138.6, 129.3, 128.5, 128.1 (d, J = 32.4 Hz), 126.6, 125.8 (q, J = 3.7 Hz), 124.6 (d, J = 270 Hz), 122.1, 120.9, 118.9, 113.6. MS (EI) m/z
338 (M+); IR(KBr) 697, 853, 1020, 1516, 2927cm-1; mp 184-185oC.
1-(3,5-bis(trifluoromethyl)phenyl)-3-phenylimidazo[1,5-a]pyridine (3k). Isolated yield: 93% (75 mg), yellow solid. 1H NMR (400
MHz, CDCl3) δ 8.41 (s, 2H), 8.29 (d, J = 7.2 Hz, 1H), 7.94–7.80 (m, 3H), 7.76 (s, 1H), 7.57 (t, J = 7.4 Hz, 2H), 7.54–7.44 (m, 1H), 6.97
(dd, J = 9.1, 6.4 Hz, 1H), 6.68 (t, J = 6.8 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 139.2, 137.3, 132.1 (q, J = 33.0 Hz), 129.6, 129.5, 129.4,
128.8, 128.6, 126.1, 123.7 (d, J = 270 Hz), 122.5, 121.9, 119.6 (q, J = 4.0 Hz), 118.3, 113.8. HRMS calc. C21H12F6N2 (M+): 406.0905,
Found: 406.0907. IR(KBr) 698, 859, 1517, 2929cm-1; mp 133-134oC.
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1-(3,5-difluorophenyl)-3-phenylimidazo[1,5-a]pyridine (3l). Isolated yield: 92% (56 mg), yellow solid. H NMR (400 MHz, CDCl3) δ
8.25 (d, J = 7.3 Hz, 1H), 7.91–7.74 (m, 3H), 7.55 (t, J = 7.5 Hz, 2H), 7.52–7.43 (m, 3H), 6.89 (dd, J = 9.0, 6.5 Hz, 1H), 6.71 (tt, J = 9.0,
2.3 Hz, 1H), 6.63 (t, J = 6.8 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 163.6 (d, J = 245 Hz), 163.5 (d, J = 245 Hz), 138.6, 138.3 (t, J =
10.4 Hz), 129.8, 129.6, 129.3, 129.2, 128.5, 128.4, 122.3, 121.2, 118.6, 113.6, 109.2, 109.1, 109.0, 108.9, 101.6 (t, J = 25.6 Hz). HRMS
calc. C19H12F2N2 (M+): 306.0969, Found: 306.0975. IR(KBr) 698, 1067, 1127, 2927cm-1; mp160-161oC.
1-(3,5-dichlorophenyl)-3-phenylimidazo[1,5-a]pyridine (3m). Isolated yield: 93% (63 mg), yellow solid. 1H NMR (400 MHz, CDCl3) δ
8.24 (d, J = 7.3 Hz, 1H), 7.84–7.79 (m, 5H), 7.56-7.49 (m, 2H), 7.48-7.45 (m, 1H), 7.24 (t, J = 1.9 Hz, 1H), 6.89 (dd, J = 9.3, 6.4 Hz, 1H),
6.68–6.58 (m, 1H). 13C NMR (101 MHz, CDCl3) δ 138.8, 138.1, 135.3, 129.8, 129.3, 129.2, 129.0, 128.5, 126.1, 124.7, 122.3, 121.2,
118.6, 113.6. HRMS calc. C19H12Cl2N2 (M+): 338.0378, Found: 338.0384. IR(KBr) 696, 1091, 1519, 2926cm-1; mp185-186oC.
1,3-diphenylimidazo[1,5-a]quinoline (3n). Isolated yield: 65% (42 mg), yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.93 (d, J = 7.4 Hz,
2H), 7.74–7.65 (m, 3H), 7.62 (d, J = 7.6 Hz, 1H), 7.59–7.53 (m, 3H), 7.49 (t, J = 7.9 Hz, 3H), 7.33 (dt, J = 10.2, 7.5 Hz, 2H), 7.17 (dd, J =
11.6, 4.2 Hz, 1H), 7.09 (d, J = 9.5 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 142.1, 134.2, 133.6, 133.3, 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, 117.6, 117.5. HRMS calc. C23H16N2 (M+): 320.1313, Found: 320.1315. IR(KBr)
696, 843, 1519, 2923 cm-1; mp134-135oC.
1-phenyl-3-o-tolylimidazo[1,5-a]pyridine (3o). Isolated yield: 91% (52 mg), yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.00 – 7.94 (m,
2H), 7.87 (d, J = 9.3 Hz, 1H), 7.62 (d, J = 7.2 Hz, 1H), 7.53–7.44 (m, 3H), 7.44-7.37 (m, 2H), 7.36–7.26 (m, 2H), 6.80 (dd, J = 9.0, 6.1
Hz, 1H), 6.54 (t, J = 6.7 Hz, 1H), 2.26 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 138.6, 137.9, 135.2, 131.2, 130.9, 130.7, 129.7, 129.3,
128.8, 126.7, 126.4, 126.2, 122.0, 119.7, 119.1, 112.9, 19.9. HRMS calc. C20H16N2 (M+): 284.1313, Found: 284.1317. IR(KBr) 696, 822,
1249, 1360, 1521, 1603, 2918cm-1; mp119-120oC.
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1-phenyl-3-m-tolylimidazo[1,5-a]pyridine (3p). Isolated yield: 93% (53 mg), yellow solid. H NMR (400 MHz, CDCl3) δ 8.08 (d, J =
7.2 Hz, 1H), 7.83 (d, J = 7.9 Hz, 1H), 7.68 (d, J = 9.2 Hz, 1H), 7.55 (s, 1H), 7.48 (d, J = 7.6 Hz, 1H), 7.35 (t, J = 7.6 Hz, 1H), 7.28 (t, J =
7.6 Hz, 1H), 7.18 (t, J = 7.1 Hz, 1H), 7.13 (d, J = 7.5 Hz, 1H), 6.61 (dd, J = 9.0, 6.5 Hz, 1H), 6.40 (t, J = 6.8 Hz, 1H), 2.32 (s, 1H). 13C
NMR (101 MHz, CDCl3) δ 138.9, 138.3, 135.1, 131.9, 130.1, 129.7, 129.3, 128.8, 128.8, 127.6, 126.8, 126.5, 125.1, 121.9, 119.7, 119.1,
113.2, 21.5. HRMS calc. C20H16N2 (M+): 284.1313, Found: 284.1315. IR(KBr) 696, 821, 1250, 1363, 1520, 2916cm-1; mp107-109oC.
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1-phenyl-3-p-tolylimidazo[1,5-a]pyridine (3q)3c. Isolated yield: 93% (53 mg), yellow solid. H NMR (400 MHz, CDCl3) δ 8.22 (d, J =
7.3 Hz, 1H), 7.97–7.89 (m, 2H), 7.84 (d, J = 9.3 Hz, 1H), 7.73 (d, J = 8.1 Hz, 2H), 7.47 (t, J = 7.8 Hz, 2H), 7.35 (d, J = 7.9 Hz, 2H), 7.30
(t, J = 7.4 Hz, 1H), 6.78 (dd, J = 9.2, 6.3 Hz, 1H), 6.57 (t, J = 6.8 Hz, 1H), 2.44 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 138.8, 138.3,
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135.1, 131.8, 129.7, 128.7, 128.3, 127.6, 127.3, 126.8, 126.5, 121.9, 119.6, 119.1, 113.1, 21.5. MS (EI) m/z 284 (M+); IR(KBr) 696, 1518,
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1601, 2915cm-1; mp137-138oC.
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3-(4-methoxyphenyl)-1-phenylimidazo[1,5-a]pyridine (3r)3c. Isolated yield: 92% (55 mg), yellow solid. H NMR (400 MHz, CDCl3) δ
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8.16 (d, J = 7.0 Hz, 1H), 7.94 (d, J = 7.5 Hz, 2H), 7.82 (d, J = 9.3 Hz, 1H), 7.76 (d, J = 8.4 Hz, 2H), 7.47 (t, J = 7.5 Hz, 2H), 7.30 (t, J =
7.3 Hz, 1H), 7.06 (d, J = 8.4 Hz, 2H), 6.86–6.70 (m, 1H), 6.55 (t, J = 6.5 Hz, 1H), 3.88 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 160.3,
138.0, 134.8, 131.5, 130.0, 128.8, 127.4, 127.0, 126.6, 122.4, 121.9, 119.7, 119.3, 114.6, 113.3, 55.5. MS (EI) m/z 300 (M+); IR(KBr) 699,
835, 1169, 1511, 2927cm-1; mp161-162oC.
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3-(4-chlorophenyl)-1-phenylimidazo[1,5-a]pyridine (3s)18. Isolated yield: 94% (57 mg), yellow solid. H NMR (300 MHz, CDCl3) 
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)  136.9, 134.74, 134.65, 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+); IR(KBr) 694, 1089, 1518, 1315, 1598, 2921cm-1; mp169-170oC.
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3-(4-fluorophenyl)-1-phenylimidazo[1,5-a]pyridine (3t)17. Isolated yield: 91% (52 mg), yellow solid. H NMR (400 MHz, CDCl3) δ
8.13 (d, J = 7.2 Hz, 1H), 7.92 (d, J = 7.3 Hz, 2H), 7.88–7.73 (m, 3H), 7.46 (t, J = 7.7 Hz, 2H), 7.30 (t, J = 7.4 Hz, 1H), 7.25-7.20 (m, 2H),
6.78 (dd, J = 9.2, 6.4 Hz, 1H), 6.57 (t, J = 6.8 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 163.0 (d, J = 249.2 Hz), 137.2, 134.9, 132.1, 130.4
(d, J = 8.3 Hz), 128.9, 127.7, 126.9, 126.7, 126.5 (d, J = 2 Hz), 121.6, 119.8, 119.3, 116.3 (d, J = 21.8 Hz), 113.5. MS (EI) m/z 288 (M+);
IR(KBr) 698, 1065, 1126, 2925cm-1; mp167-168oC.
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1-phenyl-3-(4-(trifluoromethyl)phenyl)imidazo[1,5-a]pyridine (3u)3c. Isolated yield: 94% (63 mg), yellow solid. H NMR (400 MHz,
CDCl3) δ 8.24 (d, J = 7.2 Hz, 1H), 7.98 (d, J = 8.1 Hz, 2H), 7.92 (d, J = 7.2 Hz, 2H), 7.86 (d, J = 9.3 Hz, 1H), 7.78 (d, J = 8.2 Hz, 2H),
7.47 (t, J = 7.7 Hz, 2H), 7.31 (t, J = 7.4 Hz, 1H), 6.83 (dd, J = 9.1, 6.4 Hz, 1H), 6.63 (t, J = 6.8 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ
136.6, 134.7, 133.8, 132.9, 130.5 (q, J = 33 Hz), 128.9, 128.42, 128.36, 127.0, 126.1 (q, J = 3.7 Hz), 124.1 (d, J = 272.1 Hz), 121.7, 120.4,
119.5, 114.1. MS (EI) m/z 338 (M+); IR(KBr) 697, 1067, 1124, 1167, 1321, 2926cm-1; mp138-139oC.
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3-(naphthalen-1-yl)-1-phenylimidazo[1,5-a]pyridine (3v). Isolated yield: 90% (58 mg), yellow solid. H NMR (400 MHz, CDCl3) δ
8.06–7.99 (m, 3H), 7.94 (dd, J = 12.3, 8.7 Hz, 2H), 7.80 (d, J = 7.0 Hz, 1H), 7.75 (d, J = 8.4 Hz, 1H), 7.68–7.58 (m, 2H), 7.57–7.43 (m,
4H), 7.31 (t, J = 7.4 Hz, 1H), 6.83 (dd, J = 9.3, 6.3 Hz, 1H), 6.49 (t, J = 6.8 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 136.9, 135.2, 134.1,
132.0, 131.7, 130.1, 128.9, 128.8, 128.7, 127.3, 127.2, 126.8, 126.5, 126.4, 125.7, 125.5, 122.3, 120.0, 119.0, 112.9. HRMS calc. C23H16N2
(M+): 320.1313, Found: 320.1319. IR(KBr) 669, 840, 1351, 2921cm-1; mp123-124oC.
3-(furan-2-yl)-1-phenylimidazo[1,5-a]pyridine (3w)18. Isolated yield: 63% (33 mg), yellow solid. 1H NMR (300 MHz, CDCl3)  8.67 (d,
J = 7.5 Hz, 1H), 7.92 (d, J = 7.5 Hz, 2H), 7.84 (d, J = 9.3Hz, 1H), 7.60 (s, 1H), 7.49-7.44 (m, 2H), 7.33-7.31 (m, 1H), 7.08 (s, 1H), 6.85-
6.80 (t, J = 15.6 Hz, 1H), 6.71-6.66 (t, J = 13.2 Hz, 1H), 6.61 (s, 1H). 13C NMR (75 MHz, CDCl3)  146.3, 142.1, 134.7, 132.4, 130.2,
128.7, 127.4, 127.0, 126.7, 123.2, 119.9, 118.9, 113.8, 111.7, 108.7. MS (EI) m/z 260 (M+); IR(KBr) 921, 1520, 1600, 2921cm-1; mp123-
124oC.
1-phenyl-3-(pyridin-2-yl)imidazo[1,5-a]pyridine (3x) Isolated yield: 31% (17 mg), yellow solid. 1H NMR (400 MHz, CDCl3) δ 10.03 (d,
J = 7.3 Hz, 1H), 8.69–8.62 (m, 1H), 8.50 (d, J = 8.1 Hz, 1H), 8.02–7.94 (m, 2H), 7.90 (d, J = 9.2 Hz, 1H), 7.80 (td, J = 7.6, 1.5 Hz, 1H),
7.50 (t, J = 7.7 Hz, 2H), 7.33 (t, J = 7.4 Hz, 1H), 7.25–7.17 (m, 1H). 13C NMR (101 MHz, CDCl3) δ 151.1, 148.2, 136.6, 135.1, 135.0,
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132.4, 129.3, 128.9, 127.1, 126.9, 126.5, 122.4, 121.8, 121.2, 118.5, 113.9. HRMS calc. C18H14N3 (M+H)+: 272.1188, Found: 272.1192.
IR(KBr) 921, 1520, 1600, 2921cm-1; mp100-101oC.
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Associated content
The 1H and 13CNMR spectra for all products. This material is available free of charge via the Internet at http://pubs.acs.org.
Note: The authors declare no competing financial interest.
Acknowledgments
We are grateful to the Natural Science Foundation of China (21302105) and the financial support from Nanyang Normal University
(ZX2015009, ZX2015010).
References
1. (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.
2. (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.
3. For selected examples, see: (a) Shibahara, F.; Kitagawa, A.; Yamaguchi, E.; Murai, T. Org. Lett. 2006, 8, 5621-5624 and references cited therein; (b)
Wang, Q.; Zhang, S.; Guo, F. F.; Zhang, B. Q.; Hu, P.; Wang, Z. Y. J. Org. Chem. 2012, 77, 11161-11166 and references cited therein; (c) Shibahara,
F.; Sugiura, R.; Yamaguchi, E.; Kitagawa, A.; Murai, T. J. Org. Chem. 2009, 74, 3566-3568; (d) Shi, Y.; Gulevich, A. V.; Gevorgyan, V. Angew.
Chem., Int. Ed. 2014, 53, 14191-14195.
4. For recent reviews on sp2 C-H amination, see: (a) Muller, P.; Fruit, C. Chem. Rev. 2003, 103, 2905-2920; (b) Davies, H. M. L.; Long, M. S. Angew.
Chem., Int. Ed. 2005, 44, 3518-3520; (c) Davies, H. M. L.; Manning, J. R. Nature 2008, 451, 417-424; (d) Collet, F.; Dodd, R. H.; Dauban, P. Chem.
Commun. 2009, 45, 5061-5074; (e) Armstrong, A.; Collins, J. C. Angew. Chem., Int. Ed. 2010, 49, 2282-2285; (f) Collet, F.; Lescot, C.; Dauban, P.
Chem. Soc. Rev. 2011, 40, 1926-1936; (g) Cho, S. H.; Kim, J. Y.; Kwak, J.; Chang, S. Chem. Soc. Rev. 2011, 40, 5068-5083; (h) Louillat, M. L.;
Patureau, F. W. Chem. Soc. Rev. 2014, 43, 901-910.
5. For recent reviews on sp3 C-H amination, see: (a) Che, C. M.; Lo, V. K. Y.; Zhou, C. Y.; Huang, J. S. Chem. Soc. Rev. 2011, 40, 1950-1975; (b)
Ramirez, T. A.; Zhao, B.; Shi, Y. Chem. Soc. Rev. 2012, 41, 931-942; For selected examples on sp3 C-H amination, see: (c) Nadres, E. T.; Daugulis, O.
J. Am. Chem. Soc. 2012, 134, 7-10; (d) Souto, J. A.; Zian, D.; Muňiz, K. J. Am. Chem. Soc. 2012, 134, 7242-7275; (e) He, G.; Zhang, Y.; Nack, W. A.;
Li, Q.; Chen, G. Angew. Chem., Int. Ed. 2013, 52, 11124-11128. (f) Yan, Y. Z.; Zhang, Y. H.; Zha, Z. G.; Wang, Z. Y. Org. Lett. 2013, 15, 2274-2277;
(g) Ilangovan, A.; Satish, G. Org. Lett. 2013, 15, 5726-5729; (h) Xue, Q.; Xie, J.; Li, H.; Cheng, Y.; Zhu, C. Chem. Commun. 2013, 49, 3700-3702; (i)
Jiang, Q.; Xu, B.; Zhao, A.; Jia, J.; Liu, T.; Guo, C. J. Org. Chem. 2014, 79, 8750-8756; (j) Lv, Y.; Li, Y.; Xiong, T.; Lu, Y.; Liu, Q.; Zhang, Q. Chem.
Commun. 2014, 50, 2367-2369. (k) Li, Q.; Huang, Y.; Chen, T.; Zhou, Y.; Xu, Q.; Yin, S.; Han, L. Org. Lett. 2014, 16, 3672-3675; (l) Zhang, X.;
Wang, M.; Lia, P.; Wang, L. Chem. Commun. 2014, 50, 8006-8009; (m) Zhao, D.; Wang, T.; Li, J. X. Chem. Commun. 2014, 50, 6471-6474; (n) Zhu,
X.; Chiba, S. Org. Bio. Chem. 2014, 12, 4567-4570; (o) Kang, T.; Kim, Y.; Lee, D.; Wang, Z.; Chang, S. J. Am. Chem. Soc. 2014, 136, 4141-4144.
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6. For examples on intramolecular sp3 C-H amination, see: Jeffrey, J. L.; Sarpong, R. Chem. Sci. 2013, 4, 4092-4106 and references cited therein.
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7. (a) Xu, K.; Hu, Y. B.; Zhang, S.; Zha, Z. G.; Wang, Z. Y. Chem. Eur. J. 2012, 18, 9793-9797; (b) Xu, K.; Fang, Y.; Yan, Z. C.; Zha, Z. G.; Wang, Z. Y.
Org. Lett. 2013, 15, 2148-2151.
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8. During the preparation of this manuscript, a nice work by Ye and Zeng described the amination reaction between pyridine aldehyde and benzylamine,
see: Li, M. Y.; Xie, Y.; Ye, Y.; Zou, Y.; Jiang, H. F.; Zeng, W. Org. Lett. 2014,16, 6232-6235. In this paper, the authors report one example of the
reaction between challenging pyridine ketone and benzylamine, however, the yield was only 42%.
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9. For examples on benzylic cation intermediate, see: Sun, C. L.; Li, B. J.; Shi, Z. J. Chem. Rev. 2011, 111, 1293-1314 and references cited therein.
10. For examples on benzylic oxidation, see: (a) Brackman, W.; Gaasbeek, C. J. Recl.Trav. Chim. Pays-Bas. 1966, 85, 257-265; (b) Semmelhack, M. F.;
Schmid, C. R.; Cortes, D. A.; Chou,C. S. J. Am.Chem. Soc. 1984, 106, 3374-3376; (c) Gamez, P.; Arends, I. W. C. E.; Reedijk, J.; Sheldon, R. A. Chem.
Comm. 2003, 2412-2415; (d) Kumpulainen, E. T. T.; Koskinen, A. M. P. Chem. Eur. J. 2009, 15, 10901-10911; (e) Hoover, J. M.; Stahl, S. S. J. Am.
Chem. Soc. 2011, 133, 16901-16910.
11. For selected examples on concenptually similar synthesis, see: (a) Kondo, T.; Yang, S.; Huh, K. T.; Kobayashi, M.; Kotachi, S.; Watanabe, Y. Chem.
Lett. 1991, 1275-1278; (b) Chen, Y. X.; Qian, L. F.; Zhang, W.; Han, B. Angew. Chem. Int. Ed. 2008, 47, 9330-9333; (c) Yu, J.; Xu, J.; Lu, M. Appl.
Organometal. Chem. 2013, 27, 606–610.
12. Maerten, E.; Sauthier, M.; Mortreux, A.; Castanet, Y. Tetrahedron 2007, 63, 682-689.
13. Basil, B.; Coffee, E. C. J.; Gell, D. L.; Maxwell, D. R.; Sheffield, D. J.; Wooldridge, K. R. H. J. Med. Chem. 1970, 13, 403-406.
14. Kim, S.-H.; Rieke, R. D. Tetrahedron Lett. 2009, 50, 5329-5331.
15. Mukhopadhyay, R.; Kundu, N. G. Tetrahedron Lett. 2000, 41, 9927-9930.
16. Reuxa, B.; Nevalainenb, T.; Raitiob, K. H.; Koskinen, A. M. P. Bio. Med. Chem. 2009, 17, 4441-4447.
17. Shibahara, F.; Yamaguchi, E.; Kitagawa, A.; Imai, A.; Murai, T. Tetrahedron 2009, 65, 5062-5073.
18. Kovtun, P. Y.; Prostota, A. Y. Chem. Heterocycl. Compd. 2000, 36, 557-559.
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