The required triazole containing aldehydes (20) were prepared via two-step sequence which features the synthesis of key starting material, (1-alkyl-1H-1,2,3-triazol-4-yl)methanol (15), which was synthesized by following the earlier reported procedures in chapter II followed by the oxidation of the product 15 by pyridiniumchlorochromate (PCC) in dichloromethane at room temperature. The various synthesized triazole containing aldehydes (20) are shown in the Table 11.
Table 11. Synthesis of 1-alkyl-1,2,3-triazole-4-carbaldehydea
Entry R(6) Product (15) Yield 15
(%)b
Product (20) Yield 20 (%)b
1 C6H5CH2 (6a) 92 82
2 4Me-C6H5CH2
(6b)
90 78
3 4Br-C6H5CH2
(6c)
86 76
4 4F-C6H5CH2
(6d)
15d N N N
F HO
90 78
5 Allyl (6e) 80 72
6 Ethoxycarbonyl methyl (6j)
78 68
aThe reactions were performed in 10 mmol scale. bIsolated yield.
All the products 15 and 20 were characterized by 1H NMR, 13C NMR spectra and HRMS.
Moreover, the structure of alcoholic triazolyl precursor (15j) was confirmed through single X-ray analysis (Figure 14, I). The X-ray data shows an intermolecular hydrogen bonding along with layered structure as shown in Figure 14, II.
I II
Figure 14. I) X-ray structure of 15j. II) A) Intermolecular H-Bonding. B) Layered-structure through intermolecular H-Bonding 15j
After the synthesis of 1-alkyl-1,2,3-triazole-4-carbaldehyde (20), the trial reactions were carried out with 1-benzyl-1,2,3-triazole-4-carbaldehyde (20a), 2-aminopyridine (21a) and phenylacetylene (22a) to optimize the reaction conditions and the obtained results are represented in Table 12. To pursue our goal, a variety of Cu(II) source were examined with different reducing agent and the best result was obtained with 5 mol%
of copper oxide nanoparticle along with 10 mol% sodium ascorbate in ethanol at 70 ˚C (Table 12). In addition Cu(I) source was also examined under the same reaction condition and it yielded to 51% (Table 12, entry 5). On screening with different polar protic (H2O, EtOH), polar aprotic (CH3CN) and nonpolar (toluene) solvents, ethanol was found to be the suitable choice for the synthesis of 2-triazolyl-imidazo[1,2- a]pyridine.
Table 12. Optimization of the reaction conditionsa
Entry Catalyst Mol % Reductant (Mol%) Solvent Time (h) Yield (%)b 1 Cu(NO3)2.
3H2O 05 NaOAs (10) EtOH 12 42
2 CuCl2 05 NaOAs (10) EtOH 12 45
3 Cu(OAc)2.2H2O 05 NaOAs (10) EtOH 12 44
4 CuSO4.
5H2O 05 NaOAs (10) EtOH 12 47
5 CuI 05 - EtOH 16 51
6 CuO Nanoparticle 05 - EtOH 18 25
7 CuO Nanoparticle 05 D-Glucose (10) EtOH 16 35
8 CuO Nanoparticle 05 D-Glucose (10) H2O 18 52
9 CuO Nanoparticle 05 NaOAs (10) H2O 16 58
10 CuCl2 05 NaOAs (10) H2O 18 31
11 CuO Nanoparticle 02 NaOAs (5) EtOH 11 75
12 CuO Nanoparticle 05 NaOAs (10) EtOH 10 84
13 CuO Nanoparticle 10 NaOAs (20) EtOH 11 78
aThe reactions were carried out using each 1 mmol of 1-benzyl-1,2,3-triazole-4-carbaldehyde (20a), 2-aminopyridine (21a) and phenylacetylene(22a). bIsolated yield.
After optimization, we have conducted a reaction with 2-aminopyridine (21a), phenylacetylene (22a) and with a variety of substituent on triazole-4-carbaldehyde such as 4-methylbenzyl (20b), 4-bromobenzyl (20c) and 4-fluorobenzyl (20d) under similar reaction conditions to obtain the desired product 23b-d with 80-82% yields (Table 13, entries 2-4). The reaction of 5-methyl-2-aminopyridine (21b) and phenylacetylene (22a) with Allyl (20e) and ethoxycarbonylmethyl (20f) substituted aliphatic triazole-4-carbaldehyde afford the required product 23e and 23f in 72% and 68% yield (Table 13, entries 5-6) respectively. Next, we prompt to investigate the present protocol with 5-methyl-2-aminopyridine (21b), 4-tert butylphenyl acetylene / phenyl acetylene and with a variety of substituted triazole-4-carbaldehyde such as benzyl (20a), 4-methylbenzyl (20b), 4-bromobenzyl (20c) and 4-fluorobenzyl (20d) derivatives under identical reaction conditions and the desired products 23g-m were obtained in 80-85% yields (Table 13, entries 7-13).
Table 13. Synthesis of 3-alkyl-2-(1-alkyl-1,2,3-triazol-4-yl)-imidazo[1,2-a]pyridinea
Entry Aldehyde (20)
R1(21) R2 (22)
Product (23) Time
(h)
Yield (%)b
01 20a 21a 22a 10 84
02 20b 21a 22a 11 80
03 20c 21a 22a 10 82
04 20d 21a 22a 09 82
05 20e 21b 22a 12 72
06 20f 21b 22a 12 68
07 20a 21b 22b 11 80
08 20b 21b 22a 10 82
09 20d 21b 22a 09 84
10 20a 21b 22a 10 85
11 20b 21b 22b 12 84
12 20c 21b 22a 10 82
13 20d 21b 22b 10 80
14 20a 21c 22c 11 75
15 20a 21c 22d 11 78
aThe reactions were performed in 0.5 mmol scale of 1-alkyl-1,2,3-triazole-4-carbaldehyde (20), aminopyridine (21) and terminal alkynes (22). bIsolated yield.
Furthermore, the reaction was also performed with benzyl triazole-4-carbaldehyde (20a), 5- chloro-2-aminopyridine (21c) and with substituted phenylacetylene such as 3-methyl (22c) and 2-methoxy (22d) under similar reaction conditions afforded the desired products 23n and 23o in 75% and 78% yield (Table 13, entries 14-15) respectively.
The structure of the compound 23c was confirmed through single-crystal X-ray analysis which is depicted in Figure 15, A. The molecule 23c shows a dimer structure
with C-H…π interaction (H17b…C10) and its layered structure embrace a spectacular supramolecular assembly which is shown in Figure 15, B & C.
(A)
(B) (C)
Figure 15. X-ray crystal structure (A), C-H…π interaction (B) and Layered structure (C) of 23c
In addition, the recyclability of the catalyst was tested with 23c. The obtained results are displayed in Table 14 and represented graphically in Figure 16A. In addition, the FESEM image of nano copper oxide catalyst after five cycles as shown in Figure 16B.
Thus, it is concluded from the table 14 that even after five cycles our expected imidazole derivative could be achieved in moderate yield which shows the catalyst CuO nanoparticle is recyclable.
Table 14. Recycling of the CuO nanoparticlea in 23c Entry No of
cycle
mmol Catalyst used
Catalyst Recovered
Time (h)
Yield (%)
01 01 07 28 25 10 81
02 02 05 20 18 11 77
03 03 04 16 13 12 72
04 04 03 12 09 14 68
05 05 02 08 5 18 58
aCuO nanoparticle was filtered from the reaction mixture and washed with dichloromethane and dried before use for next cycle.
A B
Figure 16. (A) Recycle of the catalyst CuO nanoparticle and (B) FESEM image of CuO nanoparticle after five times recycling
The present protocol was further explored for the synthesis of 2-(2-(1-alkyl-1,2,3- triazol-4-yl)-imidazo[1,2-a]pyridin-3-yl)ethanol using propagyl alcohol (14), with different substituted triazole-4-carbaldehyde (20) and amidine (21) in the presence of catalytic amount of copper oxide nanoparticle along with sodium ascorbate under analogues reaction conditions and it offered the corresponding products 24a-e with 72- 78% yield which is depicted in Table 15.
Table 15. Synthesis of 2-(2-(1-alkyl-1,2,3-triazol-4-yl)-imidazo[1,2-a]pyridin-3-yl)ethanola
Entry Aldehyde (20)
R1(21) Product (24) Time
(h)
Yield (%)b
01 20c 21a 12 72
02 20a 21b 11 74
03 20c 21b 11 76
04 20b 21b 10 78
05 20b 21a 11 76
aThe reactions were carried out in 0.5 mmol scale of 1-alkyl-1H-1,2,3-triazole-4-carbaldehyde (20), aminopyridine (21) and propargyl alcohol (14). bIsolated yield.
The plausible mechanism for the formation of 2-triazolyl-imidazo[1,2-a]pyridine is outlined in Scheme 34. The copper(II) nanoparticle is reduced in the presence of sodium ascorbate to form copper(I) and then it forms a σ-adduct with the alkyne moiety to give the species I.The triazolyl aldehyde 20 reacts with amidine 21 to form imine II. Then the reaction of species I with imine II produces intermediate III.
Subsequently, intermediate III undergoes favorable 5-exo-dig cyclisation to form IV and it is followed by a 1,3-hydrogen shift to afford 2-triazolyl-imidazo[1,2-a]pyridine 23.
1,3 H -shift
Scheme 34. Plausible mechanism for the formation of 2-triazolyl-imidazo[1,2-a]pyridine