A new synthesis of pyrroles

Article abstract of DOI:10.1039/b207061h

The radical reaction between an N-ethylsulfonylenamide and an α-xanthyl ketone gives an intermediate γ-keto imine which spontaneously ring-closes to the pyrrole.

Full text of DOI:10.1039/b207061h

A new synthesis of pyrroles
Béatrice Quiclet-Sire, Frédérique Wendeborn (née Bertrand)† and Samir Z. Zard*
Laboratoire de Synthèse Organique associé au CNRS, Ecole Polytechnique, F-91128 Palaiseau Cedex,
France. E-mail: zard@poly.polytechnique.fr; Fax: +33 (0)1 6933 3851; Tel: +33 (0)1 6933 4872
Received (in Cambridge, UK) 18th July 2002, Accepted 8th August 2002
First published as an Advance Article on the web 3rd September 2002
The radical reaction between an N-ethylsulfonylenamide
and an a-xanthyl ketone gives an intermediate g-keto imine
which spontaneously ring-closes to the pyrrole.
initially quite straightforward. In practice, however, we encoun-
tered some unexpected difficulty in implementing the desired
radical chain process.
Initial experiments with xanthate 2a (Table 1) were dis-
appointing. The yield of pyrrole was low and extensive
decomposition of enesulfonamide 1 was observed under
conditions which proved satisfactory in our previous studies
with sulfones.5
The pyrrole ring corresponds to one of the more basic
heteroaromatic structures. It is an essential building block for
the construction of porphyrins and a key element in a number of
biologically active compounds.1 It is not surprising therefore
that, over the years, much effort has been invested in the design
and development of synthetic routes to pyrroles.1,2 As part of
our ongoing studies on the radical chemistry of xanthates and of
sulfonyl radicals,3 we have found a new access to this
fundamental ring system which complements existing synthetic
pathways.
Table 1 Synthesis of pyrrolesa
The reaction sequence outlined in Scheme 1 summarises our
approach. Ethylsulfonyl radicals generated by the action of an
initiator on enesulfonamide 1 can undergo loss of sulfur dioxide
to give ethyl radicals, which can undergo a reversible sequence
of addition–fragmentation to a xanthate such as 2 to provide an
acetonyl radical 3 and diethyl xanthate 4 as co-product. In turn,
addition of radical 3 to enesulfonamide 1 gives imine 5 after the
expulsion of an ethylsulfonyl radical, thus closing the radical
chain loop. The iminyl group in intermediate 5 is ideally located
with respect to the carbonyl of the ketone to ensure a
spontaneous ring closure to the pyrrole 6 with the concomitant
formation of a water molecule.
The synthesis of the enesulfonamide 1 was readily accom-
plished starting with ethyl pyruvate and ethylsulfonamide by an
adaptation of a literature procedure.4‡ We had previously
exploited the loss of sulfur dioxide from alkylsulfonyl radicals
as a means for the tin-free allylation and vinylation of aliphatic
xanthates and iodides,5 and the present extension seemed
Scheme 1 Reaction pathway to pyrroles.
† Present address: Ciba Specialty Chemicals, Schwarzwaldallee 215, CH-
4002 Basel, Switzerland.
a Yields in parenthesis are based on recovered starting material.
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vacuum. Purification of the residue by column chromatography over silica
gel using a heptane+ethyl acetate gradient gave pure ethylsulfonylenamide
1 as a pale yellow oil (2.7 g, 44%); IR (film, cm21): 3277, 1715, 1635; 1H
NMR (300 MHz; CDCl3) d ppm: 6.95 (bs, 1H), 5.73 (dd, J = 1.2 Hz, JA =
16.1 Hz, 2H), 4.32 (q, J = 7.0 Hz, 2H), 3.17 (q, J = 7.4 Hz, 2H), 1.37 (t,
J = 7.4 Hz, 3H), 1.36 (t, J = 7.0 Hz, 3H); 13C NMR (50 MHz; CDCl3) d
ppm: 163.1, 131.5, 106,5, 64.3, 50.5, 13.9, 8.3. Calc. For C7H13NO4S: C,
40.57; H, 6.32. Found: C, 40.61; H, 6.38.
Typical experimental procedure for the synthesis of pyrroles: A solution
of ehylsulfonylamide 1 (2 mmol) and xanthate 3 (1 mmol) in a 5+1 mixture
of heptane and chlorobenzene (3 ml) were heated to reflux under argon for
15 min. Solid AIBN (2.5 mol%) was added every hour and, when TLC
indicated the consumption of the sulfonylenamide 1, a further portion (2
mmol) was added (this process was in some cases repeated once again; the
total reaction time did not exceed 10–11 h). The mixture was then cooled,
concentrated under partial vacuum and the residue purified by column
chromatography over silica gel.
Scheme 2 Isomerisation and decomposition of N-sulfonylenamide 1.
Our problems appeared to be due to a competing chain
reaction, pictured in Scheme 2, causing an irreversible iso-
merisation of 1 into the highly reactive imine 7.§ Such
rearrangements involving N-arylsulfonylenamides were ob-
served by Hertler some years ago.6 Further uncontrolled
condensation reactions of imine 7 can lead to the liberation of
ammonia, which in turn causes the destruction of the starting
xanthate and chain inhibition.
§ Unlike the present case, the addition of ethyl sulfonyl radicals to ethyl
allyl sulfone and related reagents used in ref. 5 is reversible and degenerate
and does not therefore interfere with the desired process.
In the light of this reasoning, we had to keep the temperature
as high as possible in order to speed up the unimolecular loss of
sulfur dioxide from ethyl sulfonyl radicals without causing
thermal decomposition of the reactants. At the same time, we
increased the dilution and added sulfonylenamide 1 in portions
as the reaction progressed in order to slow down the unwanted
rearrangement. With these experimental modifications,‡ the
yield of pyrrole became acceptable, as shown by the examples
compiled in Table 1. Various functional groups are tolerated
and both aromatic or heteroaromatic (e.g. thiophene in example
6e) and aliphatic substituents may be incorporated.
Even though the procedure has not been completely opti-
mised in this preliminary study and room for improvement
certainly exists, the present radical based, tin-free approach
provides an expedient route to pyrroles with a useful substitu-
tion pattern, using readily available starting materials and
reagents.
1 (a) A. Jones and G. P. Bean, The Chemistry of Pyrroles, Academic Press,
London, 1977; (b) A. Jones, Pyrroles, Wiley, New York, 1990; (c) L. N.
Sobenina, A. I. Mikhaleva and B. A. Trofimov, Russ. Chem. Rev. (Engl.
Transl.), 1989, 58, 163.
2 For some recent syntheses of pyrroles, see: (a) V. Kameswaran and B.
Jiang, Synthesis, 1997, 530; (b) D. W. Knight, A. L. Redfern and J.
Gilmore, Chem. Commun, 1998, 2207; (c) H. Shiraishi, T. Nishitani, S.
Sakaguchi and Y. Ishii, J. Org. Chem., 1998, 63, 6234; (d) H. Shiraishi,
T. Nishitani, T. Nishihana, S. Sakaguchi and Y. Ishii, Tetrahedron, 1999,
55, 13957; (e) M. Mori, K. Hori, M. Akashi, M. Hori, Y. Sato and M.
Nishida, Angew. Chem., Int. Ed., 1998, 37, 636; (f) U. Ademitsu, M.
Tanaka, T. Inoue and N. Ono, Synthesis, 1999, 471; (g) L. Selic and N.
Stanovnik, Synthesis, 1999, 530; (h) M. Friedrich, A. Wächtler and A. de
Meijere, Synlett, 2002, 619; (i) B. Gabriele, G. Salerno, A. Fazio and F.
B. Campana, Chem. Commun., 2002, 1408; (j) P. M. T. Ferreira, H. L. S.
Maia and L. S. Monteiro, Tetrahedron Lett., 2002, 43, 4491.
3 S. Z. Zard, in “Radicals in Organic Synthesis”, Ed. P. Renaud and M.
Sibi, Wiley VCH, Weinheim, 2001, p. 90–108; S. Z. Zard, Angew.
Chem., Int. Ed. Engl., 1997, 36, 672; B. Quiclet-Sire and S. Z. Zard,
Phosphorus, Sulfur, Silicon, 1999, 153–154, 137.
We thank Rhodia and the CNRS for generous financial
support to one of us (FW) and Dr Virginie Pevere for many
friendly discussions.
4 Y. Yonezawa, C. Shin, Y. Ono and J. Yoshimura, Bull. Chem. Soc. Jpn.,
1980, 53, 2905; B. M. Trost and G. R. Dake, J. Am. Chem. Soc., 1997,
119, 7595.
5 F. Le Guyader, B. Quiclet-Sire, S. Seguin and S. Z. Zard, J. Am. Chem.
Soc., 1997, 117, 7410; B. Quiclet-Sire, S. Seguin and S. Z. Zard, Angew.
Chem., Int. Ed., 1998, 37, 2864; F. Bertrand, B. Quiclet-Sire and S. Z.
Zard, Angew. Chem., Int. Ed., 1999, 38, 1943; F. Bertrand, F. Le
Guyader, L. Liguori, G. Ouvry, B. Quiclet-Sire, S. Seguin and S. Z. Zard,
C. R. Acad. Sci Paris, Chemistry, 2001, 114, 547. For extensions of this
chemistry by other groups, see: C. Ollivier and P. Renaud, J. Am. Chem.
Soc., 2000, 122, 6496; S. Kim, H.-J. Song, T.-L. Choi and J.-Y. Yoon,
Angew. Chem. Int., 2001, 40, 2524.
Notes and references
‡
Synthesis of sulfonylenamide 1: Ethyl pyruvate (3.5 g, 29.8 mmol) and
phosphorus oxychloride (1.9 g, 20.4 mmol) were added to a solution of
ethanesulfonamide (3.9 g, 35.8 mmol) in anhydrous acetonitrile (44 ml)
under an inert atmosphere and the resulting solution heated to reflux for 4
h. After cooling, the medium was diluted with dichloromethane and washed
with aqueous sodium bicarbonate solution until neutral pH. The aqueous
phases were extracted once more with dichloromethane and the combined
organic phases dried over sodium sulfate and concentrated under partial
6 W. R. Hertler, J. Org. Chem., 1974, 39, 3219.
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