Trimethylaluminium-Facilitated Direct Amidation of Carboxylic Acids

Abstract

Free carboxylic acids are converted into amides in moderate to high yields in the presence of a stoichiometric amount of trimethylaluminium and amines at 90 ˚C after 1 hour.

amide - amidation - trimethylaluminium - carboxylic ­acid - Lewis acid

References and Notes

1a Bracher F. J. Prakt. Chem.  1999,  341:  88 

1b Suzuki K. Nagasawa T. In Encyclopedia of Reagents for Organic Synthesis   Vol. 7:  Paquette LA. John Wiley and Sons; Sussex / UK: 1995.  p.5186-5189  

1c Maruoka K. In Lewis Acid Reagents: A Practical Approach   Yamamoto H. Oxford University Press; Oxford / UK: 1999.  Chap. 2.

2a Basha A. Lipton M. Weinreb SM. Tetrahedron Lett.  1977,  48:  4171 

2b Hirabayashi T. Itoh K. Sakai S. Ishii Y. J. Organomet. Chem.  1970,  25:  33 

Direct amide formation under thermal alone condition goes back to 1858. See:

3a Arnold K. Davies B. Giles RL. Grosjean C. Smith GE. Whiting A. Adv. Synth. Catal.  2006,  348:  813 ; and references cited therein; also see ref. 8 below

Reviews of general amidation:

3b Benz G. In Comprehensive Organic Synthesis   Vol. 6:  Trost BM. Fleming I. Heathcock CH. Pergamon Press; New York: 1991.  Chap. 2.3.

3c Ziegler T. Science of Synthesis   Vol. 21:  Thieme; Stuttgart: 2005.  p.43-75  

3d Although not cited in any reviews of amidation, we did uncover an isolated report during our exaustive literature search where a procedure was described for lactam formation of α,ω-amino acids [H₂N(CH₂)_nCO₂H, n equals to 3, 4, or 5] using 2 equiv of triethylaluminium. There was no description on the scope and limitation of this transformation beyond these three intramolecular examples of unfunctionalized and unsubstituted α,ω-amino acids, i.e., intermolecular amidation, functional-group compatibility, steric and electronic factors were not examined. Furthermore, no rationale of the reaction was offered. See: Yamamoto Y. Furuta T. Chem. Lett.  1989,  5:  797 

4 Comerford JW. Clark JH. Macquarrie DJ. Breeden SW. Chem. Commun.  2009,  2562 

5

Typical Procedures
Into a 8 mL 15 × 75 mm tube was added amine (1.0 mmol) and a solution/suspension of 1.0 mmol acid in toluene (1.0 mL). To this mixture was then added 2 M Me₃Al/toluene solution (Aldrich, 0.50 mL). The resulting mixture, usually a clear solution, was then shaken at 90 ˚C for 1 h. The reaction mixture was then diluted with CH₂Cl₂ (50 mL), and the resulting organic solution was washed with 20% NH₄OH (50 mL). The organic layer was then concentrated to give pure product usually in greater high purity (>90%). The less pure products were purified further via crystallization in a mixture of hexane and EtOAc or flash column chromatog-raphy.

6

Yield based on LC-MS evaporative light scattering detection (ELSD) using a gradient H₂O-MeCN-TFA mobile phase on a 5 micron reverse phase C8 analytical column (4.6 × 50 mm).

7

Product confirmed by ^¹H NMR, LC-MS, HPLC- and HRMS.
Biphenyl-4-carboxylic Acid Cyclohexylmethylamide
^¹H NMR (300 MHz, CD₃OD): δ = 7.87 (d, J = 8.0 Hz, 2 H), 7.69 (d, J = 8.8 Hz, 2 H), 7.64 (d, J = 7.2 Hz, 2 H), 7.44 (t, J = 7.2 Hz, 2 H),7.35 (t, J = 7.6 Hz, 1 H), 3.22 (d, J = 6.8 Hz, 2 H), 1.77 (t, J = 15.2 Hz, 4 H), 1.65 (m, 2 H), 1.25 (m, 3 H), 0.99 (m, 2 H). ^¹³C NMR (500 MHz, CD₃OD): δ = 168.00, 144.33, 140.11, 133.41, 128.81, 127.84, 127.65, 126.91, 126.81, 46.12, 38.11, 30.91, 26.42, 25.86. MS: m/z = 294.2 [M + H]. HRMS: m/z calcd: 294.1858 [M + H]; found: 294.1866.

8a Tang P. Org. Synth.  2004,  81:  262 

8b Ishihara K. Ohara S. Yamamoto H. J. Org. Chem.  1996,  61:  4196 

8c Maki T. Ishihara K. Yamamoto H. Tetrahedron  2007,  63:  8645 

8d For catalytic amidation effected by boronic acid at milder conditions, see: Al-Zoubi RM. Marion O. Hall DG. Angew. Chem. Int. Ed.  2008,  47:  2876 

8e Arnold K. Davies B. Herault D. Whiting A. Angew. Chem. Int. Ed.  2008,  47:  2673