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A simple modification to improve the generality of Terry's 3,4-disubstituted pyrrole synthesis

G. Fernando Cortés, J. Z. Gustavo Avila and G. Luis Angel Maldonado

Instituto de Química, UNAM, Circuito Exterior, Ciudad Universitaria, Coyoacán 04510, México D.F., México

Abstract

The reaction between 1-benzenesulfonamidopropan-2-one and electrophilic olefins affords substituted pyrrolidines, that are readily converted into 3,4-disubstituted pyrroles by standard methods.

Synthesis of 2,3-disubstituted pyrroles according to Terry, Jackson, Kenner and Konis

The condensation of an alkyl N-tosyl glycinate with a vinyl ketone in basic media has been reported (Terry, W.G.; Jackson, A.H., Kenner, G.W.; Konis G., J. Chem. Soc., 1965, 4389) to give substituted pyrrolidinols by tandem Michael and intramolecular aldol type reactions. Dehydration and base promoted elimination of the p-toluenesulfinate anion then gives 3-substituted-2-pyrrole carbolic esters:

Scheme 1

Synthesis of 3,4-disubstituted pyrroles according to Terry, Jackson, Kenner and Konis

The method can be easily adapted for the preparation of 3,4-disubstituted pyrroles if one starts from the appropriately substituted enone. However, the carboxylic ester group in the initially obtained 3,4-disubstituted-2-pyrrole carboxylic ester should be removed, thus adding two extra steps to the sequence:

Scheme 2

Incidentally, in this case the R' and R2 substituents can hardly be synthetically useful functional groups.

Exchange of functional groups, the key to out proposal (I)

Now we wish to report a simple structural modification in the involved substrates of Scheme 1, which leads directly to 3,4-disubstituted pyrroles (without the need to remove "extra" groups) and in which at least one substitutent is functionalized and therefore prone to further synthetic elaboration.

We reasoned that an exchange in the functional groups in the original substrates of the Terry method (Scheme 1), would give a new pair of starting materials (now an a,b-unsaturated ester and an a-arenesulfonamido ketone) which by the same sequence of reactions would afford 3,4-disubstituted pyrroles.

Exchange of functional groups, the key to out proposal (II)

Scheme 3

Hence, this simple modification changes the substitution pattern in the final product, affording directly the most difficulty accessible 3,4-disubstituted pyrrole.

Synthesis of 1-benzenesulfonamidopropan-2-one

At present, all our experiments have been performed with the title compound as the a-arenesulfonamido ketone component. This compound has been obtained quite easily as indicated (85% overall yield)

Scheme 4

Spectral data: IR(CHCl3) 3350, 1730,1344,1165,1095 cm-1; 1H NMR (CDCl3, 200 MHz) d 2.10 (s,3H), 3.90 (d,J=4.6,2H; collapses to a singlet with D2O), 5.40 (broad, NH), 7.55 (m,3H), 7.90 (m,2H); MS (70eV) m/z (%) 214(M++1,1), 213 (M+, 1), 170 (100), 141 (78), 77 (73), 51 (12), 43 (19).

Synthesis of methyl 4-methyl-3-pyrrole carboxyalte

Condensation of 1-benzenesulfonamidopropan-2-one with methyl acrylate in the presence of NaH (1.1 equiv.) in a 1:1 mixture of THF-DMSO at 0 oC, gave a crystalline pyrrolidine (mp 110 oC) as a single diastereoisomer. Dehydration to the d3-pyrroline with POCl3-pyridine and aromatization by elimination of the benzenesulfinate anion with ButOK or (much simpler) DBU in refluxing THF, gave the title known (Van Leusen, A.M.; Siderius, H.; Hoogenboom, B.E.; Van Leusen, D. Tetrahedron Lett., 1972, 5337) pyrrole in ~ 40% overrall yield.

Scheme 5

Other 4-methyl-3-substituted pyrroles obtained in this work

Two other electrophilic olefins (acrylonitrile and MVK) have also been used in the general sequence, affording the corresponding 4-methyl-3-substituted pyrroles in comparable yields (~ 35-40% overall )

Scheme 6

Conclusion

  1. With MVK we have found optimal yields in the first step when performed at low temperature (-78 oC)
  2. With MVK no 2,3-disubstituted pyrrole has been detected (potentially formed by enolate equilibration prior to aldol cyclization in the first step)
  3. In striking contrast to the methyl acrylate case, the corresponding cyclic aldols with MVK and acrylonitrile are obtained as nearly 1:1 mixtures of diastereoisomers
  4. The Terry method and ours, proceed through the same C3-C4 and N-C5 bond forming processes
  5. In the Terry method, one starting material behaves as a double donor reagent (the N-tosyl glycinate) and the other as a double acceptor reagent (the enone). Both substituents in the resulting pyrrole come from the enone
  6. In our modification, each substrate has the double function of being donor-acceptor reagents and each one contributes with one substituent in the final pyrrole