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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Carboxylative cyclization of substituted propenyl ketones using CO2: transition-metal-free synthesis of [small alpha]-pyrones

Carboxylative cyclization of substituted propenyl ketones using CO2: transition-metal-free synthesis of [small alpha]-pyrones

Green Chem., 2016, 18,4181-4184

DOI: 10.1039/C6GC01346E, Communication

Wen-Zhen Zhang, Ming-Wang Yang, Xiao-Bing Lu
Carboxylative cyclization of substituted 1-propenyl ketones via [gamma]-carboxylation using CO₂ provides an efficient, straightforward, and transition-metal-free access to [small alpha]-pyrone compounds.

http://pubs.rsc.org/en/Content/ArticleLanding/2016/GC/C6GC01346E?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+rss%2FGC+%28RSC+-+Green+Chem.+latest+articles%29#!divAbstract

Carboxylative cyclization of substituted propenyl ketones using CO₂: transition-metal-free synthesis of α-pyrones

Wen-Zhen Zhang,*^a   Ming-Wang Yang^a and   Xiao-Bing Lu^a  

*Corresponding authors

^aState Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian, P. R. China
E-mail: zhangwz@dlut.edu.cn

Green Chem., 2016,18, 4181-4184

DOI: 10.1039/C6GC01346E

 

Carbon dioxide is a green carboxylative reagent due to its non-toxic and renewable properties. Described herein is a carboxylative cyclization of substituted 1-propenyl ketones via γ-carboxylation using CO₂, which provides an efficient, transition-metal-free and straightforward access to important α-pyrone compounds from easily available substrates and CO₂.

 

 

////////////Carboxylative cyclization, substituted propenyl ketones, CO2,  transition-metal-free synthesis,  [small alpha]-pyrones

4,6,7,8,9,10-hexahydro-1H-6,10-methanopyrazino[2,3-h][3]benzazepine-2,3-dione.

Chemical structures of Varenicline Tartrate and degradant product (DP-I).........4,6,7,8,9,10-hexahydro-1H-6,10-methanopyrazino[2,3-h][3]benzazepine-2,3-dione.

(A) ¹H NMR spectrum of DP-I. (B) Proton decoupled ¹³C NMR spectrum of DP-I.


UHPLC-ToF MS⁺ of DP-I.

The impurity obtained as pale white crystals. mp 71–73. 

RP-UHPLC, tR = 1.8 min (98.5% purity).

MS (ESI, 70 eV): [M + H⁺] m/z 244. 

FT-IR (KBr), v, cm⁻¹ 3371, 3319, 3279, 3173, 3005, 2808, 1696, 1678, 1588, 1406, 1388, 1338, 1305, 1264, 1135, 1067, 873, 790, 680, 569, 485.

¹H NMR (400 MHz, DMSO-d₆ +D₂O, TMS): δ 7.2 (s, 2H, H-7,8), 3.1–3.4 (m, 6H, H-11,13,14 & 16),2.3 (m, 1H, H-12), 2.0 (d, 1H, 11.2 Hz, H-12).

¹³C NMR (100 MHz, DMSO-d₆, TMS): δ 173.8 (C-2,3), 155.1 (C-5,6), 137.6 (C-9,10), 125.1 (C-7,8), 38.8 (C-11), 37.9 (C-12), 38.8 (C-13), 45.8 (C-14), 48.6 (C-16).

UHPLC ToF MS+: m/z [M + H⁺].Calcd for C₁₃H₁₃N₃O₂: 244.1086; found: 244.1082.

Based on the above spectral data, the molecular formula of DP-I is C₁₃H₁₃N₃O₂ and the corresponding structure was characterized as 4,6,7,8,9,10-hexahydro-1H-6,10-methanopyrazino[2,3-h][3]benzazepine-2,3-dione.

PMC full text:

Sci Pharm. 2012 Apr-Jun; 80(2): 329–336. Published online 2012 Mar 20. doi:  10.3797/scipharm.1201-08

http://dx.doi.org/10.3797/scipharm.1201-08

(E)-3-(3-((phenylamino)sulfonyl)phenyl)acrylic acid

Preparation of (E)-3-(3-((phenylamino)sulfonyl)phenyl)acrylic acid (6)

Malonic acid (145 g, 1.4 mol) was added in batches to a solution of 3-formyl-N-phenylbenzenesulfonamide 5 (240 g, 0.9 mol) and piperidine (18 mL, 0.2 mol) in pyridine (700 mL), then the mixture was stirred at 105–110 °C for 8.5 h. When TLC analysis indicated the disappearance of 5, the reaction mixture was cooled to ambient temperature and slowly poured into chilled 5% aqueous solution of sodium hydroxide (2.4 L) below 20 °C (pH: 9–10). The reaction mixture was washed with EA (1.2 L), and the separated organic layer was extracted with 5% aqueous solution of sodium hydroxide (600 mL). The aqueous layers were combined and cooled to 10–20 °C, then it was acidified slowly with 50% sulfuric acid (600 mL) below 20 °C (pH: 1–2). After the solution stirred for an additional 30 min at 15–20 °C, the solid obtained was collected by filtration and then washed with water (2.4 L) followed by n-hexane (1 L). The filter cake was dried in a vacuum oven at 50 °C to afforded colorless solid (E)-3-(3-((phenylamino)sulfonyl)phenyl)acrylic acid (244 g, 83%). mp 154–156 °C. 1H NMR (400 MHz, DMSO-d6) δ = 12.62 (bs, 1H), 10.32 (s, 1H), 8.01 (s, 1H), 7.94 (d, J = 7.8 Hz, 1H), 7.75 (d, J = 7.8 Hz, 1H), 7.63–7.56 (m, 2H), 7.24 (m, 2H), 7.11–7.01 (m, 3H), 6.55 (d, J = 16.0 Hz, 1H). MS (ESI):m/z = 326.0 [M+Na] +.

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KHAJURAHO, MADHYA PRADESH, INDIA

Khajuraho Group of Monuments

The Khajuraho Group of Monuments is a group of Hindu and Jain temples in Madhya Pradesh, India, about 175 kilometres southeast of Jhansi. They are one of the UNESCO World Heritage Sites in India.Wikipedia

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3-Formyl-N-phenylbenzenesulfonamide

Preparation of 3-Formyl-N-phenylbenzenesulfonamide (5)

Pyridine (96 mL, 1.5 mol) was added to a solution of aniline (118 mL, 1.3 mol) in EA (600 mL), and the mixture was stirred at 0–5 °C. Then the solution of 3-formylbenzenesulfonyl chloride 4 (200 g, 1.0 mol) in EA (400 mL) was added slowly to the reaction mixture over 1.5 h while maintaining the reaction temperature below 5 °C. The solution was stirred at 0–5 °C for 1 h and then at ambient temperature for 19 h. When the reaction was deemed to be complete with no 4 detected by TLC, the reaction mixture was washed with a 10% aqueous solution of hydrochloric acid (two portions of 500 mL) followed by washing with water (500 L), 5% aqueous solution of sodium bicarbonate (500 mL), and then brine (500 mL); dried with sodium sulfate anhydrous; filtered; and concentrated to afford yellow solid 3-formyl-N-phenylbenzenesulfonamide (242 g, 93%). Crude 5was used directly into next step. A sample of purified 5 as a white solid was analyzed as follows.

1H NMR (CDCl3, 400 MHz) δ = 10.38 (s, 1H), 10.00 (s, 1H), 8.29 (s, 1H), 8.05 (d, J = 7.8 Hz, 1H), 8.00 (d, J = 7.8 Hz, 1H), 7.62 (t, J = 7.8 Hz, 1H), 7.27–7.23 (m, 2H), 7.16–7.01 (m, 3H).

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KHAJURAHO, MADYA PRADESH, INDIA

Khajuraho Group of Monuments

The Khajuraho Group of Monuments is a group of Hindu and Jain temples in Madhya Pradesh, India, about 175 kilometres southeast of Jhansi. They are one of the UNESCO World Heritage Sites in India.Wikipedia

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