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Preparation of Weinreb Amides from Carboxylic Acid via CDI Activation; 5-bromo-N-methoxy-N-methylfuran-2-carboxamide

SyntheticPage 571
DOI: 10.1039/SP571
Submitted Sep 01, 2012, published Sep 13, 2012
Christopher Kelly (christopher.b.kelly@uconn.edu)
A contribution from Leadbeater Group


			Reaction Scheme: <IMG src="/images/empty.gif"><IMG alt="" src="/images/empty.gif"><STRONG>Preparation of Weinreb Amides from Carboxylic Acid <EM>via</EM> CDI Activation</STRONG><IMG alt="" src="/images/empty.gif"><IMG src="/images/empty.gif">

Chemicals Used

5-Bromo-2-furoic acid (99%, Alfa Aesar)
1,1′-Carbonyldiimidazole (98% Synquest Laboratories)
N,O-Dimethylhydroxylamine, Hydrochloride Salt (98% Synquest Laboratories)
Pyridine  (≥99.0%, ACS Reagent Grade, Sigma-Aldrich)
Dicholormethane (≥99.5%, ACS Reagent Grade, Sigma-Aldrich)

Procedure

To a 500 mL round bottom flask equipped with stir bar was added 5-bromo-2-furanoic acid (6.69 g, 35 mmol, 1 equiv) and dichloromethane (120 mL, ≈ 0.3M). To this stirred heterogenous1 solution was added 1,1’-carbonyl diimadazole (6.24 g, 38.5 mmol, 1.1 equiv.) in one portion, turning the solution from milky white to a clear yellow and resulting in the evolution of CO2 gas.2 The now yellow solution was allowed to stir for 45 minutes. At this time, N-O-dimethylhydroxylamine hydrochloride (3.76 g, 38.5 mmol, 1.1 equiv) was added all at once turning the solution a cloudy white. The reaction mixture was stirred for six hours. The reaction mixture was then quenched with 50 mL of 1 M HCl3 and stirred vigorously for 10 minutes. After this time, the solution was transferred to a separatory funnel and the layers were separated. The aqueous layer was extracted with DCM (2 X 100 mL). The combine organic layers were washed with 1 M HCl (100 mL), deionized water (100 mL) and a 1:1 mixture of brine and a saturated sodium bicarbonate solution (200 mL). The organic layer was dried with Na2SO4 and the solvent was removed in vacuo by rotary evaporation  to afford the pure amide, 5-bromo-N-methoxy-N-methylfuran-2-carboxamide (5.70 g, 70%).

Author's Comments

We've found this reaction to be an excellent alternative to synthesizing Weinreb amides. It is very useful in systems where synthesis of the acid chloride from the carboxylic acid is complicated by sensitive moieties (i.e. alkenes etc).

Notes:
1. As long as the acid has some solubility in DCM, the reaction with CDI will proceed quite readily. If no reaction is observed (i.e. if the reaction does not become homogeneous) THF can be added as a co-solvent. 
2. While gas is evolved, minimal to no heat is given off and hence cooling is not required
3. In the case of acid-sensitive or basic species, alternative workup conditions are as follows: After reaction completion, quench with an equal volume a 1 M NaOH solution relative to the solvent. Extract the aqueous layer with DCM (twice with  a volume equal to the initial solvent volume), wash with brine (once with a volume equal to the initial solvent volume ), dry with NaSO4 and remove the solvent in vacuo via rotary evaporation

Data

1H NMR (CDCl3, 400 MHz) δ ppm 3.17 (s, 3 H) 3.62 (s, 3 H) 6.32 (d, J=3.42 Hz, 1 H) 6.94 (d, J=3.67 Hz, 1 H)
13
C NMR
(CDCl3, 100 MHz) δ ppm 32.98 (CH3) 61.34 (CH3) 113.54 (CH) 119.64 (CH) 126.31 (C) 147.57 (C) 157.75 (C)
GC-MS (EI) 235 ([M]+, 81Br  7%), 233([M]+, 79Br  7%), 175 (81Br  98%), 173 (79Br  100%), 119 (81Br 24%), 117 (79Br  24%) 66 (16%) 38 (19%).


Lead Reference

Rudzinski, D. M.; Kelly C. B.; Leadbeater, N. E. Chem. Commun. 2012, 48, 9610

Other References

Coe, J. W.;  Bianco, K. E.;  Boscoe, B. P.; Brooks, P. R.;  Cox, E. D.; Vetelino, M. G. J. Org. Chem. 2003, 68, 9964.

Supplementary Information

H NMR (H NMR Furan.jpg)
C13 NMR (C13 Furan.jpg)

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Get structure file (.cdx, .sk2, .mol)

Keywords: Amidation, amides, carboxylic acids, CDI Activation, heterocyclic compounds, nucleophilic, substitution, Weinreb Amide

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