Rapid, metal-free and aqueous synthesis of imidazo[1,2-a]pyridine under ambient conditions

Rapid, metal-free and aqueous synthesis of imidazo[1,2-a]pyridine under ambient conditions

Green Chem., 2016, Advance Article
DOI: 10.1039/C6GC01601D, Communication

 Open Access

  This article is licensed under a Creative Commons Attribution 3.0 Unported Licence.

Michael R. Chapman, Maria H. T. Kwan, Georgina E. King, Benjamin A. Kyffin, A. John Blacker, Charlotte E. Willans, Bao N. Nguyen
A route to access the privileged imidazo[1,2-a]pyridine scaffold in one step, 1-10 minutes using only aqueous NaOH, is reported.

Rapid, metal-free and aqueous synthesis of imidazo[1,2-a]pyridine under ambient conditions

Michael R. Chapman,^a   Maria H. T. Kwan,^a   Georgina E. King,^a  Benjamin A. Kyffin,^a   A. John Blacker,^a  Charlotte E. Willans*^a and   Bao N. Nguyen*^a  

*Corresponding authors

^aInstitute of Process Research and Development, School of Chemistry, University of Leeds, Leeds, UK
E-mail: b.nguyen@leeds.ac.uk

Green Chem., 2016, Advance Article

DOI: 10.1039/C6GC01601D

see...........http://pubs.rsc.org/en/Content/ArticleLanding/2016/GC/C6GC01601D?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+rss%2FGC+%28RSC+-+Green+Chem.+latest+articles%29#!divAbstract

 

see http://pubs.rsc.org/en/content/articlehtml/2016/gc/c6gc01601d

 

A novel, rapid and efficient route to imidazo[1,2-a]pyridines under ambient, aqueous and metal-free conditions is reported. The NaOH-promoted cycloisomerisations of N-propargylpyridiniums give quantitative yield in a few minutes (10 g scale). A comparison of common green metrics to current routes showed clear improvements, with at least a one order of magnitude increase in space-time-yield.

 

Scheme 1 Synthetic methods to assemble imidazo[1,2-a]pyridines.

Fig. 1 A scaled up reaction setup. (a) before reaction; (b) during addition of 1a (zoomed in); (c) phase separation at the end of the reaction (zoomed in).

2-Aminopyridine (6.12 g, 65.0 mmol), propargyl bromide (11.6 g of an 80 wt.% solution in toluene, 78 mmol, 1.2 equiv) and 2-propanol (200 mL) charged to a round bottomed flask and stirred at 50 C for 2 hours. After which, a pale yellow solid precipitated from solution. This was filtered and washed with diethyl ether (2 x 30 mL) followed by drying in vacuo to give product 1a in 11.1 g (52 mmol, 80% isolated yield). To a stirring solution of NaOH (1.90 g, 47.5 mmol) in deionised H2O (70 mL) was added 2-amino-1- (2-propynyl)pyridinium bromide 1a (10.0 g, 47.0 mmol) via powder addition funnel (a) over a period of 5 minutes. Immediately upon addition, the solution phase turned yellow (b – d) and a yellow oil became dispersed as a distinct separate phase (e). The oil (product) was subsequently extracted into EtOAc (2 × 30 mL) (f), dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to afford imidazo[1,2-a]pyridine 2a as a spectroscopically pure pale yellow oil. Yield: 6.12 g, 98% yield.

2-Amino-1-(2-propynyl)pyridinium bromide 1a: 1
1 M. Bakherad, H. N. –Isfahani, A. Keivanloo, N. Doostmohammadi, Tetrahedron Lett. 2008, 49, 3819-3822
2-Aminopyridine was reacted according to the general procedure (vide supra), affording the product as a colourless solid. Yield: 0.88 g, 83% yield.
1H NMR (300 MHz, D2O): δ (ppm) 8.08 (d, J = 6.9 Hz, 1H, pyH), 7.93 (t, J = 16.2, 8.4 Hz, 1H, pyH), 7.17 (d, J = 8.4 Hz, 1H, pyH), 7.01 (t, J = 14.1, 6.9 Hz, 1H, pyH), 5.06 (d, J = 2.7 Hz, 2H, CH2), 3.18 (t, J = 5.1, 2.7 Hz, 1H, C≡CH).
13C{1H} NMR (100 MHz, D2O): δ (ppm) 153.8, 143.1, 138.5, 115.2, 113.9, 78.6, 73.2, 43.5.
HR-MS (ESI+ ): m/z 133.0756 [C8H9N2] + , calcd. [M – Br]+ 133.0760.
Anal. calcd. (%) for C8H9N2Br: C 45.10, H 4.26, N 13.15; found C 45.40, H 4.30, N 13.20.
Lit. data:1 1H NMR (500 MHz, DMSO-d6) 8.72 (s, 2H, NH2), 8.23 – 6.85 (m, 4H, pyH), 5.12 (s, 2H, CH2), 3.85 (s, 1H, CH).
13C NMR (125 MHz, DMSO-d6) 154.5, 143.6, 139.8, 115.8, 114.0, 80.5, 76.0, 43.9.
1H NMR  BELOW 1a

2-Methylimidazo[1,2-a]pyridine 2a:1 2-Amino-1-(2-propynyl)pyridinium bromide (1a) was reacted according to the general procedure (vide supra), affording the product as a colourless oil which solidifies under vacuum at room temperature. Yield: 0.13 g, 100% yield.
1H NMR (300 MHz, CDCl3): δ (ppm) 8.24 (dt, J = 6.6, 2.1, 0.9 Hz, 1H, pyH), 7.58 (d, J = 9.0 Hz, 1H, pyH), 7.49 (s, 1H, imH), 7.20 (m, 1H, pyH), 6.80 (td, J = 9.0, 6.6, 0.9 Hz, 1H, pyH), 2.41 (d, J = 0.9 Hz, 3H, CH3).
13C{1H} NMR (75 MHz, CDCl3): δ (ppm) 143.2, 140.2, 126.5, 126.1, 115.2, 113.3, 110.2, 13.1.
HR-MS (ESI+ ): m/z 133.0759 [C8H9N2] + , calcd. [M + H]+ 133.0760.
Anal. calcd. (%) for C8H8N2: C 72.70, H 6.10, N 21.10; found C 72.70, H 6.50, N 20.75.
Lit. data:1 1H NMR (500 MHz, DMSO-d6) 8.29 (s, 1H, CH), 7.59 – 7.03 (m, 4H, pyH), 1.21 (s, 3H, CH3).
13C NMR (125 MHz, DMSO-d6) 148.0, 140.0, 137.1, 130.8, 130.1, 116.2, 114.5, 34.1.
1 M. Bakherad, H. N. –Isfahani, A. Keivanloo, N. Doostmohammadi, Tetrahedron Lett. 2008, 49, 3819-3822

 

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(EP2857404) IMIDAZO[1,2-b]PYRIDAZINE DERIVATIVE AS KINASE INHIBITOR

IMIDAZO[1,2-b]PYRIDAZINE DERIVATIVE AS KINASE INHIBITOR (Thu, 09 Apr 2015) 
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DAIICHI SANKYO CO LTD

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[Reference Example 39]

tert-Butyl N-[1-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]methyl]cyclopropyl]carbamate

[0201]  

[Step 1]

tert-Butyl N-[1-(hydroxymethyl)cyclopropyl]carbamate

[0202]  A solution of 1-(N-tert-butoxycarbonylamino)cyclopropanecarboxylic acid (5 g) in tetrahydrofuran was cooled to -20°C. Isobutyl chloroformate (3.24 ml) and N-methylmorpholine (2.74 ml) were added thereto, and the mixture was stirred at the same temperature as above for 20 minutes. Then, sodium borohydride (1.12 g) and water (1 ml) were added thereto, and the mixture was further stirred at room temperature for 40 minutes. Water was added to the reaction solution, followed by extraction with ethyl acetate. The extract was washed with water and saturated saline in this order and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane-ethyl acetate) to obtain the title compound (4.24 g).
¹H-NMR (CDCl₃) δ: 0.81-0.85 (4H, m), 1.44 (9H, s), 3.43 (1H, br s), 3.59 (2H, d, J = 4.8 Hz), 5.07 (1H, br s).

[Step 2]

[1-(tert-Butoxycarbonylamino)cyclopropyl]methyl methanesulfonate

[0203]  The title compound (3.93 g) was obtained by the same procedures as in step 1 of Reference Example 25 using the compound (3.21 g) obtained in the preceding step 1.
¹H-NMR (CDCl₃) δ: 0.92-0.96 (4H, m), 1.44 (9H, s), 3.03 (3H, s), 4.25 (2H, s), 5.06 (1H, br s).

[Step 3]

tert-Butyl N-[1-[(4-bromophenoxy)methyl]cyclopropyl]carbamate

[0204]  The title compound (0.43 g) was obtained by the same procedures as in step 2 of Reference Example 25 using the compound (2.05 g) obtained in the preceding step 2. ¹H-NMR (CDCl₃) δ: 0.89-0.92 (4H, m), 1.43 (9H, s), 3.94 (2H, s), 5.11 (1H, br s), 6.77 (2H, d, J = 9.1 Hz), 7.36 (2H, d, J = 9.1 Hz).

[Step 4]

tert-Butyl N-[1-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]methyl]cyclopropyl]carbamate

[0205]  The title compound (0.39 g) was obtained by the same procedures as in step 2 of Reference Example 1 using the compound (0.43 g) obtained in the preceding step 3. ¹H-NMR (CDCl₃) δ: 0.89-0.92 (4H, m), 1.33 (12H, s), 1.42 (9H, s), 3.99 (2H, s), 5.14 (1H, br s), 6.88 (2H, d, J = 8.5 Hz), 7.73 (2H, d, J = 8.5 Hz).