Methods of Non-a-Amino Acid Synthesis, 2nd Edition

65

3

Conjugate Addition

Reactions

Amines and many amine surrogates are nucleophiles in conjugate addition reactions

(the Michael reaction).

1

It is therefore not surprising that they add to conjugated acid

derivatives to give amino acids. This strategic approach to their synthesis is signi-

cant, and for that reason it has been segregated into a separate chapter.

3.1 AMMONIA AND AMINE NUCLEOPHILES

Ammonia is sufciently nucleophilic that addition to the double bond of a conju-

gated ester is possible, without attack at the acyl carbon, although the conjugate

addition tends to be reversible. Amines undergo similar conjugate addition. In both

cases, the product is a 3-aminopropanoic acid derivative (a β-amino acid derivative).

The most common method for producing substituted β-amino acids is via conju-

gate addition to conjugated acid derivatives, usually esters. This reaction is sometimes

called an aza-Michael reaction.

2

A chemoenzymatic variation led to an enantioselec-

tive synthesis of β-amino acids.

3

Just as ammonia reacts as a nucleophile in a Michael

addition with α,β-unsaturated carbonyl derivatives, amines add to conjugated acids

such as acrylic acid to give β-amino acids (3-aminopropanoic acids).

4

Methylamine,

aniline, dimethylamine, pyrrolidine, and morpholine add to acrylic acid to give the

corresponding 3-N-substituted or N,N-disubstituted aminopropanoic acid derivative.

4

Since ammonia or an amine react as bases, an acid-base reaction with conju-

gate carboxylic acids is inevitable, and this fact can limit the yield and utility of

the reaction. Yields are often better when conjugated esters are used as a substrate

rather than the acid itself, as shown by the addition of diethylamine to ethyl acrylate,

which gave ethyl 3-(N,N-diethyl-amino)propionate (1) in 87% yield.

5

Similarly, tert-

butylamine added to give an 87% yield of 2.

6

The reaction can also be done using an

1

(a) Michael, A. J. Prakt. Chem. 1887, 35, 379; (b) Bergmann, E.D.; Gingberg, D.; Pappo, R. Org. React.

1959, 10, 179; (c) Perlmutter, P. Conjugative Addition Reactions in Organic Synthesis. Pergamon Press,

Oxford, 1992; (d) see Smith, M.B. Organic Synthesis, 3rd ed. Wavefunction, Inc./Elsevier, Irvine, CA/

London, England, 2010, pp. 877–888; (e) Smith, M.B. March’s Advanced Organic Chemistry, 7th ed.

John Wiley & Sons, Hoboken, NJ, 2013, pp. 943–949.

2

See (a) Yamagiwa, N.; Qin, H.; Matsunaga, S.; Shibasaki, M. J. Am. Chem. Soc. 2005, 127, 13419; (b)

Munro-Leighton, C.; Blue, E.D.; Gunnoe, T.B. J. Am. Chem. Soc. 2006, 128, 1446; (c) Smith, M.B.

March’s Advanced Organic Chemistry, 7th ed. John Wiley & Sons, Hoboken, NJ, 2013, p. 946.

3

Strompen, S.; Weiß, M.; Ingram, T.; Smirnova, I.; Gröger, H.; Hilterhaus, L.; Liese, A. Biotechn.

Bioeng. 2012, 109, 1479.

4

Jolidon, S.; Meul, T. Eur. Pat. Appl. EP 144,980 [Chem. Abstr. 1986, 105:43325p].

5

Weisel, C.A.; Taylor, R.B.; Mosher, H.S.; Whitmore, F.C. J. Am. Chem. Soc. 1945, 67, 1071.

6

Robinson, J.B.; Thomas, J. J. Chem. Soc. 1965, 2270.