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Synthesis 2016; 48(03): 351-356
DOI: 10.1055/s-0035-1560375
paper
© Georg Thieme Verlag Stuttgart · New York

Zinc Iodide Catalyzed Synthesis of 3-Aminoimidazo[1,2-a]pyridines from 2-Aminopyridines and α-Amino Carbonyl Compounds

Xu Han
a   State Key Laboratory of Applied Organic Chemistry, Department of Chemistry, Lanzhou University, Lanzhou, Gansu, 730000, P. R. of China   Email: hgs@lzu.edu.cn
,
Chaowei Ma
a   State Key Laboratory of Applied Organic Chemistry, Department of Chemistry, Lanzhou University, Lanzhou, Gansu, 730000, P. R. of China   Email: hgs@lzu.edu.cn
b   Department of Chemistry and Environmental Engineering, Xinjiang Institute of Engineering, Urumqi, Xinjiang, 830091, P. R. of China
,
Zhaoyang Wu
a   State Key Laboratory of Applied Organic Chemistry, Department of Chemistry, Lanzhou University, Lanzhou, Gansu, 730000, P. R. of China   Email: hgs@lzu.edu.cn
,
Guosheng Huang*
a   State Key Laboratory of Applied Organic Chemistry, Department of Chemistry, Lanzhou University, Lanzhou, Gansu, 730000, P. R. of China   Email: hgs@lzu.edu.cn
› Author Affiliations
Further Information

Publication History

Received: 01 September 2015

Accepted after revision: 23 October 2015

Publication Date:
26 November 2015 (online)

 
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Abstract

A concise approach to 3-aminoimidazo[1,2-a]pyridines is developed via the zinc iodide catalyzed reaction of 2-aminopyridines and α-amino carbonyl compounds in the presence of oxygen. This novel and user-friendly protocol employing diverse and easily available substrates affords the desired products in good to excellent yields.


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Key words

3-aminoimidazo[1,2-a]pyridines - zinc iodide - heterocycles - 2-aminopyridines - α-amino carbonyls

Imidazo[1,2-a]pyridines have received significant attention owing to their broad spectrum of biological activities,[1] for example, antibacterial,[2] antifungal,[3] antiviral,[4] etc. Some derivatives of this heterocycle can be used for the treatment of patients suffering from certain cancers,[5] diabetes,[6] an array of neurological syndromes,[7] and infective diseases.[8] Moreover, as a result of their remarkable structures, they can be used as fluorescent probes.[9] Since imidazo[1,2-a]pyridines play an increasingly significant role in the pharmaceutical industry, research toward developing new and more efficient approaches to this important scaffold remains an interesting challenge.

Hence, diverse reaction methods have been reported, as pioneered by three different research groups in 1998,[10] utilizing three-component reactions. Being highly efficient processes, multicomponent reactions (MCRs)[11] have become very popular and have inspired a range of synthetic methods for the formation of 3-aminoimidazo[1,2-a]pyridines. Most of them involve reactions of an isocyanide, an aldehyde and a 2-aminoazine in the presence of an ionic liquid,[12] a Lewis acid [Yb(OTf)3/AgOTf,[13] CeCl3·7H2O/NaI[14]] or a transition metal (Pd).[15] In addition, a microwave-assisted synthesis has also been reported.[16] However, the use of toxic and corrosive reagents and the limited scope represent disadvantages to these reported procedures.

Herein, we report a novel method for the preparation of 3-aminoimidazo[1,2-a]pyridines starting from 2-aminopyridines and α-amino carbonyl compounds, promoted by the Lewis acid, zinc iodide, under mild conditions. Compared to the previously described reactions, this approach employed a lower catalyst loading and less toxic reagents.

At the beginning of our investigation, the reaction between readily available 2-aminopyridine (1a) and 1-phenyl-2-(p-tolylamino)ethan-1-one (2b) was conducted in the presence of cerium(III) chloride and oxygen at 80 °C for 12 hours in isopropyl alcohol to give the desired product, 2-phenyl-N-(p-tolyl)imidazo[1,2-a]pyridin-3-amine (3ab) in 55% yield (Table [1], entry 1).

Subsequently, several other Lewis acids were examined including zinc chloride, zinc bromide, zinc triflate and samarium(III) triflate (Table [1], entries 2–5), however, none of these gave satisfactory yields of the desired product. Zinc iodide, as the catalyst, demonstrated improved activity and provided a higher, but still unsatisfactory 77% yield of product 3ab (Table [1], entry 6). At the same time, we also tested several different solvents including dimethyl sulfoxide and N,N-dimethylformamide (Table [1], entries 7 and 8), however, both were abandoned due to the low yields obtained. According to the possible reaction mechanism, a certain amount of water was generated which might have influenced the reaction outcome. In order to confirm our assumption, 4 Å molecular sieves (4 Å MS) (100 mg) were added to the reaction. To our delight, the yield increased to 89% (Table [1], entry 9). Ethanol and propan-1-ol (Table [1], entries 12 and 13) were also tested as solvents, but were less efficient compared to isopropyl alcohol.

Table 1 Optimization of the Reaction Conditionsa

Entry

Catalyst

Additive

Solvent, atmosphere

Yield (%)b

 1

CeCl3

–

i-PrOH, O2

55

 2

ZnCl2

–

i-PrOH, O2

50

 3

ZnBr2

–

i-PrOH, O2

64

 4

Zn(OTf)2

–

i-PrOH, O2

50

 5

Sm(OTf)3

–

i-PrOH, O2

52

 6

ZnI2

–

i-PrOH, O2

77

 7

ZnI2

–

DMSO, O2

34

 8

ZnI2

–

DMF, O2

45

 9

ZnI2

4 Å MS

i-PrOH, O2

89

10

–

4 Å MS

i-PrOH, O2

30c

11

ZnI2

4 Å MS

i-PrOH, air

72

12

ZnI2

4 Å MS

EtOH, O2

65

13

ZnI2

4 Å MS

PrOH, O2

84

14

ZnI2 d

4 Å MS

i-PrOH, O2

56

15

ZnI2 e

4 Å MS

i-PrOH, O2

91

a Reaction conditions: 1a (0.2 mmol), 2b (0.2 mmol), catalyst (0.06 mmol), additive (100 mg), solvent (1 mL), O2 or air (1 atm), 12 h, 80 °C. Reactions were conducted in a Schlenk tube.

b Yield of isolated product.

c Reaction was performed without any catalyst.

d ZnI2 (0.03 mmol) was used as the catalyst.

e ZnI2 (0.2 mmol) was used as the catalyst.

Using a catalyst loading of 0.03 mmol zinc iodide led to a poor yield of only 56%, whereas increasing the quantity to 0.2 mmol resulted in an improved yield of 91% (Table [1], entries 14 and 15), albeit only marginally higher than that obtained in Table [1], entry 9. As a result, a 30% catalyst loading was selected as optimum.

Table 2 Scope of the α-Amino Carbonyl Compounds 2 for the Synthesis of 3-Aminoimidazo[1,2-a]pyridines under the Optimized Reaction Conditionsa,b

a Reaction conditions: 1a (0.2 mmol), 2 (0.2 mmol), ZnI2 (0.06 mmol), 4 Å MS (100 mg), i-PrOH (1 mL), O2 (1 atm), 12 h, 80 °C. Reactions were conducted in a Schlenk tube.

b Yield of isolated product.

A control experiment carried out with air gave product 3ab in only 72% yield (Table [1], entry 11). The reaction without a Lewis acid gave the expected product in a significantly lower yield of 30% (Table [1], entry 10). From the viewpoint of atom economy, a molar ratio of 1a/2b/zinc iodide of 1:1:0.3, and a reaction temperature of 80 °C in isopropyl alcohol under an oxygen atmosphere were chosen as the optimum reaction conditions.

Next, we examined the scope of this reaction applying the optimized conditions. Product 3aa, without any substituents on the phenyl rings, was obtained in a yield of 79%. Different α-amino carbonyl compounds 2 were then tested as reagents (Table [2]). Substrates possessing electron-donating groups on the phenyl rings (methyl, dimethyl, tert-butyl) all gave good yields of the corresponding products 3ab–ae. The presence of a methyl group at position R1 (3ab) of substrate 2 had similar impact on the yield compared to that with a methyl substituent located at position R2 (3ad) (Table [2]). Lower yields of the target products 3af–ai were typically obtained when employing α-amino carbonyl compounds substituted with electron-withdrawing halogen groups (R1 and R2). Overall, the nature of the substituent(s) on the aromatic rings did not influence significantly the yield of the product. For example, a fluoro (3af), bromo (3ai) or methoxy (3aj) group at position R1 resulted in the expected products in yields of 74%, 72% and 79%, whilst a chloro (3ag) or a bromo (3ah) group at position R2 led to the products in 82% and 77% yields. The structure of product 3ag was further determined by X-ray crystallographic analysis (Figure [1]).

Zoom Image
Figure 1 ORTEP representation of the structure of 3ag (CCDC 1437741), showing the atom-labelling scheme; thermal ellipsoids are displayed at the 50% probability level

A range of substituted 2-aminopyridines 1 was also evaluated (Table [3]). The introduction of a methyl group at different positions on the pyridine ring led to the formation of the desired products (3ba–da) in good yields. However, when the methyl group was located at C-6 of the 2-aminopyridine, the desired product (3ea) was obtained in only 62% yield; this indicated that steric hindrance was more influential in this case. Other electron-donating groups such as methoxy (3fa) and benzyloxy (3ga) resulted in product yields of 74% and 52%, respectively. A 2-aminopyridine possessing an electron-withdrawing chloro group at C-4 gave a low yield of the corresponding product 3ha. Although reacting for a longer time, bromo-substituted 2-aminopyridine 2 did not react to give the target product 3ia.

Table 3 Scope of the 2-Aminopyridines 1 for the Synthesis of 3-Aminoimidazo[1,2-a]pyridines under the Optimized Reaction Conditionsa,b

a Reaction conditions: 1 (0.2 mmol), 2a (0.2 mmol), ZnI2 (0.06 mmol), 4 Å MS (100 mg), i-PrOH (1 mL), O2 (1 atm), 12 h, 80 °C. Reactions were conducted in a Schlenk tube.

b Yield of isolated product.

c Reaction was performed for 18 h. NR = no reaction.

Based on the results obtained above, a plausible mechanism for the catalytic reaction of 2-aminopyridine (1a) and 1-phenyl-2-(phenylamino)ethan-1-one (2a) is proposed (Scheme [1]). Initially, catalyzed by the Lewis acid, 1a reacts with 2a to form imine A,[17] which exists is in equilibrium with imine B. Cyclization of B then gives intermediate C; hydrogen transfer then produces intermediate D. Finally, the presence of oxygen as an oxidant promotes the formation of the product, N,2-diphenylimidazo[1,2-a]pyridin-3-amine (3aa).[18]

Zoom Image
Scheme 1 Proposed reaction mechanism

In summary, we have developed a novel and convenient method for the zinc iodide catalyzed synthesis of imidazo[1,2-a]pyridines starting from 2-aminopyridines and α-amino carbonyl compounds. This reaction is applicable for the synthesis of biologically and pharmaceutically relevant imidazo[1,2-a]pyridines. The ready availability and low toxicity of the starting materials and operational simplicity of the process are the main advantages of this method.

All chemicals were purchased from commercial suppliers and were used without further purification. Solvents were dried and purified according to standard procedures before use. The products were purified by flash column chromatography over Qingdao Haiyang Chemical Plant silica gel (200–300 mesh). Petroleum ether (PE) refers to the fraction boiling in the 40–80 °C range. Melting points were determined in open capillaries using a Gallenkamp melting point apparatus and are uncorrected. 1H NMR (400 MHz) and 13C NMR (101 MHz) spectra were recorded using a Bruker Avance III 400 spectrometer. Copies of the spectra are provided in the Supporting Information. High-resolution mass spectrometry was performed using a Bruker Daltonics APEX II spectrometer.

3-Aminoimidazo[1,2-a]pyridines; Typical Procedure

An oven-dried Schlenk tube was evacuated and backfilled with O2 three times. 2-Aminopyridine (1a) (0.2 mmol), 1-phenyl-2-(phenylamino)ethanone (2a) (0.2 mmol), ZnI2 (0.06 mmol), 4 Å MS (100 mg) and i-PrOH (1 mL) were added under an O2 atm, and the mixture was stirred at 80 °C for 12 h. The mixture was cooled to r.t. and then extracted with EtOAc (3 × 15 mL). The combined organic phase was dried over anhydrous Na2SO4, filtered and the solvent evaporated in vacuo. The crude residue was purified by column chromatography (PE–EtOAc, 1:2).


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N,2-Diphenylimidazo[1,2-a]pyridin-3-amine (3aa)

Yield: 45.2 mg (79%); yellow solid; mp 218–220 °C.

1H NMR (400 MHz, DMSO-d 6): δ = 8.23 (s, 1 H), 8.10–8.01 (m, 2 H), 7.94 (d, J = 6.8 Hz, 1 H), 7.63 (d, J = 9.1 Hz, 1 H), 7.38 (dd, J = 8.4, 7.0 Hz, 2 H), 7.29 (ddt, J = 10.8, 9.4, 4.3 Hz, 2 H), 7.13 (dd, J = 8.3, 7.1 Hz, 2 H), 6.91 (td, J = 6.8, 1.1 Hz, 1 H), 6.76–6.68 (m, 1 H), 6.56–6.45 (m, 2 H).

13C NMR (101 MHz, DMSO-d 6): δ = 145.55, 141.75, 137.43, 133.68, 129.50, 128.40, 127.45, 126.42, 125.06, 123.03, 118.91, 118.48, 117.11, 112.87, 112.20.

HRMS (FT-ICR): m/z [M + H]+ calcd for C19H16N3: 286.1339; found: 286.1336.


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2-Phenyl-N-(p-tolyl)imidazo[1,2-a]pyridin-3-amine (3ab)

Yield: 53.4 mg (89%); yellow solid; mp 216–218 °C.

1H NMR (400 MHz, CDCl3): δ = 8.00 (d, J = 7.1 Hz, 2 H), 7.81 (d, J = 6.8 Hz, 1 H), 7.63 (d, J = 9.1 Hz, 1 H), 7.36 (t, J = 7.5 Hz, 2 H), 7.29 (d, J = 7.2 Hz, 1 H), 7.24–7.15 (m, 1 H), 7.02 (d, J = 8.0 Hz, 2 H), 6.75 (t, J = 6.7 Hz, 1 H), 6.50 (d, J = 8.1 Hz, 2 H), 5.54 (s, 1 H), 2.26 (s, 3 H).

13C NMR (101 MHz, CDCl3): δ = 142.88, 142.45, 139.41, 133.64, 130.53, 129.37, 128.81, 128.02, 127.29, 125.15, 123.04, 118.69, 117.87, 113.68, 112.32, 20.69.

HRMS (FT-ICR): m/z [M + H]+ calcd for C20H18N3: 300.1495; found 300.1491.


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N-(3,4-Dimethylphenyl)-2-phenylimidazo[1,2-a]pyridin-3-amine (3ac)

Yield: 53.4 mg (85%); yellow solid; mp 220–221 °C.

1H NMR (400 MHz, DMSO-d 6): δ = 8.10–8.02 (m, 2 H), 7.99 (s, 1 H), 7.90 (d, J = 6.8 Hz, 1 H), 7.61 (d, J = 9.1 Hz, 1 H), 7.38 (dd, J = 8.3, 7.0 Hz, 2 H), 7.33–7.23 (m, 2 H), 6.94–6.84 (m, 2 H), 6.37 (d, J = 2.4 Hz, 1 H), 6.18 (dd, J = 8.0, 2.5 Hz, 1 H), 2.06 (d, J = 1.4 Hz, 6 H).

13C NMR (101 MHz, DMSO-d 6): δ = 143.41, 141.64, 137.35, 137.07, 133.75, 130.42, 128.38, 127.38, 126.41, 125.93, 124.98, 123.05, 119.31, 117.06, 114.33, 112.09, 110.14, 19.67, 18.38.

HRMS (FT-ICR): m/z [M + H]+ calcd for C21H20N3: 314.1652; found: 314.1656.


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N-Phenyl-2-(p-tolyl)imidazo[1,2-a]pyridin-3-amine (3ad)

Yield: 55.2 mg (92%); yellow solid; mp 236–237 °C.

1H NMR (400 MHz, CDCl3): δ = 7.89 (d, J = 8.2 Hz, 2 H), 7.82 (dd, J = 6.8, 1.2 Hz, 1 H), 7.63 (dt, J = 9.1, 1.1 Hz, 1 H), 7.24–7.14 (m, 5 H), 6.90–6.83 (m, 1 H), 6.75 (td, J = 6.8, 1.1 Hz, 1 H), 6.62–6.56 (m, 2 H), 5.61 (s, 1 H), 2.34 (s, 3 H).

13C NMR (101 MHz, CDCl3): δ = 144.95, 142.87, 139.64, 137.93, 130.65, 130.02, 129.54, 127.18, 125.15, 122.95, 120.07, 117.94, 117.78, 113.67, 112.32, 21.50.

HRMS (FT-ICR): m/z [M + H]+ calcd for C20H18N3: 300.1495; found: 300.1493.


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N-(4-tert-Butylphenyl)-2-phenylimidazo[1,2-a]pyridin-3-amine (3ae)

Yield: 47.9 mg (70%); yellow solid; mp 238–240 °C.

1H NMR (400 MHz, DMSO-d 6): δ = 8.07 (dt, J = 7.1, 1.3 Hz, 3 H), 7.93 (dt, J = 6.8, 1.2 Hz, 1 H), 7.61 (dt, J = 9.1, 1.1 Hz, 1 H), 7.39 (t, J = 7.6 Hz, 2 H), 7.31–7.25 (m, 2 H), 7.18–7.12 (m, 2 H), 6.90 (td, J = 6.8, 1.1 Hz, 1 H), 6.46–6.40 (m, 2 H), 1.20 (s, 9 H).

13C NMR (101 MHz, DMSO-d 6): δ = 142.99, 141.67, 140.60, 137.38, 133.76, 128.38, 127.38, 126.40, 126.13, 124.96, 123.11, 119.26, 117.06, 112.49, 112.12, 33.58, 31.33.

HRMS (FT-ICR): m/z [M + H]+ calcd for C23H24N3: 342.1965; found: 342.1960.


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N-(4-Fluorophenyl)-2-phenylimidazo[1,2-a]pyridin-3-amine (3af)

Yield: 45.0 mg (74%); yellow solid; mp 194–196 °C.

1H NMR (400 MHz, DMSO-d 6): δ = 8.20 (s, 1 H), 8.07–8.02 (m, 2 H), 7.96 (dt, J = 6.8, 1.2 Hz, 1 H), 7.64–7.61 (m, 1 H), 7.39 (dd, J = 8.3, 7.0 Hz, 2 H), 7.33–7.25 (m, 2 H), 6.98 (t, J = 8.9 Hz, 2 H), 6.92 (td, J = 6.8, 1.1 Hz, 1 H), 6.52–6.45 (m, 2 H).

13C NMR (101 MHz, DMSO-d 6): δ = 155.63 (d, J = 232 Hz), 142.01, 141.74, 137.39, 133.60, 128.40, 127.45, 126.37, 125.08, 122.97, 119.06, 117.11, 115.95 (d, J = 22 Hz), 113.81 (d, J = 8 Hz), 112.23, 40.13, 39.92, 39.71, 39.50, 39.29, 39.08, 38.87.

HRMS (FT-ICR): m/z [M + H]+ calcd for C19H13FN3: 304.1245; found: 304.1251.


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2-(4-Chlorophenyl)-N-phenylimidazo[1,2-a]pyridin-3-amine (3ag)

Yield: 52.5 mg (82%); yellow solid; mp 218–220 °C.

1H NMR (400 MHz, CDCl3): δ = 7.94 (d, J = 8.5 Hz, 2 H), 7.82 (d, J = 6.9 Hz, 1 H), 7.64 (d, J = 9.1 Hz, 1 H), 7.31 (d, J = 8.6 Hz, 2 H), 7.25–7.17 (m, 3 H), 6.88 (t, J = 7.4 Hz, 1 H), 6.78 (td, J = 6.8, 1.1 Hz, 1 H), 6.61–6.55 (m, 2 H), 5.62 (s, 1 H).

13C NMR (101 MHz, CDCl3): δ = 144.39, 142.78, 138.36, 133.72, 131.76, 129.90, 128.76, 128.28, 125.38, 122.78, 120.11, 118.07, 117.67, 113.40, 112.41.

HRMS (FT-ICR): m/z [M + H]+ calcd for C19H15ClN3: 320.0949; found: 320.0947.


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2-(4-Bromophenyl)-N-phenylimidazo[1,2-a]pyridin-3-amine (3ah)

Yield: 56.1 mg (77%); yellow solid; mp 228–230 °C.

1H NMR (400 MHz, DMSO-d 6): δ = 8.43 (s, 1 H), 8.03 (dd, J = 8.3, 1.4 Hz, 2 H), 7.97–7.94 (m, 1 H), 7.63 (d, J = 9.1 Hz, 1 H), 7.39 (dd, J = 8.4, 7.0 Hz, 2 H), 7.32–7.26 (m, 4 H), 6.92 (td, J = 6.8, 1.1 Hz, 1 H), 6.49–6.44 (m, 2 H).

13C NMR (101 MHz, DMSO-d 6): δ = 144.97, 141.87, 137.50, 133.52, 132.12, 128.47, 127.56, 126.39, 125.22, 123.00, 118.29, 117.17, 114.98, 112.37, 109.47.

HRMS (FT-ICR): m/z [M + H]+ calcd for C19H15BrN3: 364.0444; found: 364.0447.


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N-(4-Bromophenyl)-2-phenylimidazo[1,2-a]pyridin-3-amine (3ai)

Yield: 52.4 mg (72%); yellow solid; mp 232–234 °C.

1H NMR (400 MHz, DMSO-d 6): δ = 8.42 (s, 1 H), 8.05–8.00 (m, 2 H), 7.95 (d, J = 6.8 Hz, 1 H), 7.63 (d, J = 9.0 Hz, 1 H), 7.39 (dd, J = 8.4, 7.0 Hz, 2 H), 7.34–7.26 (m, 4 H), 6.92 (td, J = 6.7, 1.2 Hz, 1 H), 6.51–6.44 (m, 2 H).

13C NMR (101 MHz, DMSO-d 6): δ = 144.97, 133.51, 132.10, 131.65, 128.45, 127.55, 126.38, 125.20, 122.99, 121.05, 118.28, 117.16, 114.97, 112.36, 109.45.

HRMS (FT-ICR): m/z [M + H]+ calcd for C19H15BrN3: 364.0444; found: 364.0438.


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N-(4-Methoxyphenyl)-2-phenylimidazo[1,2-a]pyridin-3-amine (3aj)

Yield: 49.9 mg (79%); yellow solid; mp 198–199 °C.

1H NMR (400 MHz, DMSO-d 6): δ = 8.06 (dd, J = 8.3, 1.3 Hz, 2 H), 7.93 (d, J = 6.9 Hz, 2 H), 7.63–7.58 (m, 1 H), 7.38 (t, J = 7.7 Hz, 2 H), 7.31–7.25 (m, 2 H), 6.90 (td, J = 6.7, 1.1 Hz, 1 H), 6.75 (d, J = 8.9 Hz, 2 H), 6.44 (d, J = 8.9 Hz, 2 H), 3.63 (s, 3 H).

13C NMR (101 MHz, DMSO-d 6): δ = 152.33, 141.61, 139.16, 137.27, 133.77, 128.37, 127.36, 126.41, 124.93, 123.03, 119.76, 117.07, 115.04, 113.79, 112.08, 55.20.

HRMS (FT-ICR): m/z [M + H]+ calcd for C20H18N3O: 316.1444; found: 316.1447.


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8-Methyl-N,2-diphenylimidazo[1,2-a]pyridin-3-amine (3ba)

Yield: 48.0 mg (80%); yellow solid; mp 198–200 °C.

1H NMR (400 MHz, DMSO-d 6): δ = 8.22 (s, 1 H), 8.11–8.03 (m, 2 H), 7.79 (d, J = 6.7 Hz, 1 H), 7.38 (t, J = 7.7 Hz, 2 H), 7.30–7.24 (m, 1 H), 7.16–7.08 (m, 3 H), 6.81 (t, J = 6.8 Hz, 1 H), 6.71 (t, J = 7.3 Hz, 1 H), 6.50 (d, J = 7.9 Hz, 2 H), 2.57 (s, 3 H).

13C NMR (101 MHz, DMSO-d 6): δ = 145.65, 142.00, 136.95, 133.82, 129.46, 128.35, 127.31, 126.55, 126.45, 123.55, 120.80, 119.27, 118.40, 112.86, 112.14, 16.13.

HRMS (FT-ICR): m/z [M + H]+ calcd for C20H18N3: 300.1495; found: 300.1501.


#

7-Methyl-N,2-diphenylimidazo[1,2-a]pyridin-3-amine (3ca)

Yield: 42.0 mg (70%); yellow solid; mp 238–240 °C.

1H NMR (400 MHz, DMSO-d 6): δ = 8.17 (s, 1 H), 8.06–8.01 (m, 2 H), 7.81 (dd, J = 6.9, 0.9 Hz, 1 H), 7.40–7.34 (m, 3 H), 7.28–7.23 (m, 1 H), 7.12 (dd, J = 8.4, 7.2 Hz, 2 H), 6.77–6.68 (m, 2 H), 6.51–6.45 (m, 2 H), 2.37 (s, 3 H).

13C NMR (101 MHz, DMSO-d 6): δ = 145.69, 142.13, 137.05, 135.51, 133.85, 129.46, 128.33, 127.25, 126.31, 122.29, 118.41, 118.38, 115.38, 114.63, 112.82, 20.77.

HRMS (FT-ICR): m/z [M + H]+ calcd for C20H18N3: 300.1495; found: 300.1489.


#

6-Methyl-N,2-diphenylimidazo[1,2-a]pyridin-3-amine (3da)

Yield: 46.8 mg (78%); yellow solid; mp 230–232 °C.

1H NMR (400 MHz, DMSO-d 6): δ = 8.16 (s, 1 H), 8.05–7.99 (m, 2 H), 7.75 (q, J = 1.3 Hz, 1 H), 7.54 (dd, J = 9.1, 1.0 Hz, 1 H), 7.36 (dd, J = 8.4, 7.0 Hz, 2 H), 7.28–7.23 (m, 1 H), 7.18–7.11 (m, 3 H), 6.74–6.68 (m, 1 H), 6.52–6.46 (m, 2 H), 2.26 (s, 3 H).

13C NMR (101 MHz, DMSO-d 6): δ = 143.37, 141.68, 138.30, 137.38, 133.76, 128.38, 127.38, 127.24, 126.41, 124.96, 123.09, 119.29, 117.07, 112.78, 112.11, 24.06.

HRMS (FT-ICR): m/z [M + H]+ calcd for C20H18N3: 300.1495; found: 300.1493.


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5-Methyl-N,2-diphenylimidazo[1,2-a]pyridin-3-amine (3ea)

Yield: 37.2 mg (62%); yellow solid; mp 236–238 °C.

1H NMR (400 MHz, DMSO-d 6): δ = 8.10–8.02 (m, 3 H), 7.45 (d, J = 8.9 Hz, 1 H), 7.35 (dd, J = 8.4, 6.9 Hz, 2 H), 7.28–7.23 (m, 1 H), 7.15 (ddd, J = 14.0, 8.7, 6.9 Hz, 3 H), 6.67 (dd, J = 7.9, 6.8 Hz, 1 H), 6.60 (d, J = 6.8 Hz, 1 H), 6.42 (s, 2 H), 2.64 (s, 3 H).

13C NMR (101 MHz, DMSO-d 6): δ = 148.11, 143.45, 139.10, 135.89, 133.75, 129.60, 128.28, 127.40, 126.56, 125.29, 119.63, 117.92, 115.32, 113.26, 112.67, 18.34.

HRMS (FT-ICR): m/z [M + H]+ calcd for C20H18N3: 300.1495; found: 300.1497.


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7-Methoxy-N,2-diphenylimidazo[1,2-a]pyridin-3-amine (3fa)

Yield: 46.8 mg (74%); yellow solid; mp 196–198 °C.

1H NMR (400 MHz, DMSO-d 6): δ = 8.12 (s, 1 H), 8.03–7.99 (m, 2 H), 7.77 (d, J = 7.4 Hz, 1 H), 7.36 (t, J = 7.5 Hz, 2 H), 7.27–7.22 (m, 1 H), 7.16–7.10 (m, 2 H), 7.01 (d, J = 2.5 Hz, 1 H), 6.71 (t, J = 7.3 Hz, 1 H), 6.61 (dd, J = 7.4, 2.5 Hz, 1 H), 6.51 (d, J = 7.9 Hz, 2 H), 3.86 (s, 3 H).

13C NMR (101 MHz, DMSO-d 6): δ = 157.73, 145.82, 143.15, 136.64, 133.90, 129.45, 128.32, 127.10, 126.13, 123.65, 118.38, 117.90, 112.82, 106.70, 94.89, 55.63.

HRMS (FT-ICR): m/z [M + H]+ calcd for C20H18N3O: 316.1444; found: 316.1447.


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8-(Benzyloxy)-N,2-diphenylimidazo[1,2-a]pyridin-3-amine (3ga)

Yield: 20.4 mg (52%); yellow solid; mp 218–220 °C.

1H NMR (400 MHz, DMSO-d 6): δ = 8.18 (d, J = 26.6 Hz, 1 H), 8.04 (td, J = 8.3, 1.5 Hz, 2 H), 7.65–7.50 (m, 3 H), 7.50–7.42 (m, 2 H), 7.42–7.33 (m, 3 H), 7.33–7.23 (m, 2 H), 7.16–7.09 (m, 2 H), 6.87–6.61 (m, 3 H), 6.50 (d, J = 7.8 Hz, 2 H), 5.35 (s, 1 H).

13C NMR (101 MHz, DMSO-d 6): δ = 147.47, 145.58, 136.68, 136.43, 136.11, 133.64, 129.45, 128.50, 128.33, 128.16, 128.12, 127.31, 126.38, 119.72, 118.45, 115.92, 112.88, 112.12, 103.58, 70.07.

HRMS (FT-ICR): m/z [M + H]+ calcd for C26H22N3O: 392.1757; found 392.1751.


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7-Chloro-N,2-diphenylimidazo[1,2-a]pyridin-3-amine (3ha)

Yield: 29.4 mg (46%); yellow solid; mp 204–206 °C.

1H NMR (400 MHz, DMSO-d 6): δ = 8.29 (s, 1 H), 8.06–7.95 (m, 3 H), 7.82 (d, J = 1.9 Hz, 1 H), 7.40 (dd, J = 8.4, 6.9 Hz, 2 H), 7.33–7.27 (m, 1 H), 7.14 (dd, J = 8.4, 7.2 Hz, 2 H), 7.01 (dd, J = 7.2, 2.1 Hz, 1 H), 6.74 (dd, J = 7.9, 6.7 Hz, 1 H), 6.52 (d, J = 7.5 Hz, 2 H).

13C NMR (101 MHz, DMSO-d 6): δ = 145.66, 141.71, 133.33, 131.13, 130.02, 129.00, 128.35, 126.96, 124.75, 120.01, 119.24, 116.12, 114.12, 113.49, 40.63, 40.43, 40.22, 40.01, 39.80, 39.59, 39.38.

HRMS (FT-ICR): m/z [M + H]+ calcd for C19H15ClN3: 320.0949; found: 320.0942.


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Acknowledgment

We thank the State Key Laboratory of Applied Organic Chemistry for financial support. We also thank a referee for helpful advice.

Supporting Information

    Supporting information for this article is available online at http://dx.doi.org.accesdistant.sorbonne-universite.fr/10.1055/s-0035-1560375.
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Zoom Image
Figure 1 ORTEP representation of the structure of 3ag (CCDC 1437741), showing the atom-labelling scheme; thermal ellipsoids are displayed at the 50% probability level
Zoom Image
Scheme 1 Proposed reaction mechanism