A versatile approach to 3-alkyl and 2,3-dialkylpyrroles

Article abstract of DOI:10.1016/S0040-4039(00)01591-4

A route is described towards N-Benzoyl-3-Alkyl and N-Benzoyl-2,3-Dialkyl pyrroles from α-Amidoketones via an intramolecular Wittig reaction to afford 4-Phenylthio-3-Pyrrolines which are then oxidised to the corresponding sulphones and aromatised by treatm

Full text of DOI:10.1016/S0040-4039(00)01591-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 8969–8972
A versatile approach to 3-alkyl and 2,3-dialkylpyrroles
Ian Burley, Biljana Bilic, Alan T. Hewson* and Jillian R. A. Newton
Division of Chemistry and Biomedical Research Centre, Sheffield Hallam University, Pond Street,
Sheffield S1 1WB, UK
Received 17 July 2000; revised 30 August 2000; accepted 14 September 2000
Abstract
A route is described towards N-benzoyl-3-alkyl and N-benzoyl-2,3-dialkyl pyrroles from a-amido-
ketones via an intramolecular Wittig reaction to afford 4-phenylthio-3-pyrrolines which are then oxidised
to the corresponding sulphones and aromatised by treatment with potassium t-butoxide. © 2000 Elsevier
Science Ltd. All rights reserved.
Keywords: pyrrolines; aromatisation; pyrroles; intramolecular Wittig.
The pyrrole unit occurs widely in a range of natural products, drugs, dyes and polymers1 and
its synthesis continues to attract attention.2–5 A wide variety of chemistry has been used, but
most of the available methods lead to a pyrrole which is substituted at various positions with
functional groups such as esters, and which requires further synthetic operations such as
reduction or hydrolysis/decarboxylation to afford the simple alkyl substituted heterocycle.
Routes to 3-alkyl pyrroles are attractive in terms of the specific importance of such compounds
in preparing conducting polymers and natural products,6 and routes to 2,3-dialkylpyrroles are
not common.7,8 We have previously reported9 a route to the pyrrole ring system which relies on
an intramolecular Wittig reaction to build up the heterocyclic ring from the readily available
Scheme 1.
* Corresponding author. Tel: +44 (0) 114 225 3075; e-mail: a.t.hewson@shu.ac.uk
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01591-4

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a-amidoketones 1, followed by functional group manipulation to afford the N-benzyl-4-phenyl-
sulphonylpyrroles 2 (Scheme 1).
Although the method is versatile in terms of R and R%, it suffers in that the ring is substituted
with the phenylsulphonyl group, which is not always easy to remove from such systems, and the
nitrogen is N-benzylated rather than being protected with a more easily removable acyl group.
We describe here a simple extension of the chemistry in Scheme 1 which circumvents both of
these problems. Treatment of the intermediate 4-phenylsulphonyl-3-pyrrolines 3a–f9 with potas-
sium tert-butoxide gave directly, in good yield, the 2,3-dialkyl pyrroles 4a–f. It is presumed that
the reaction proceeds by deconjugation of the vinyl sulphone, followed by elimination of
benzene sulphinic acid (Scheme 2); the hindered base appears not to react with the N-COPh
group during the aromatisation process. N-Acyl pyrroles are known to readily hydrolyse with
aqueous hydroxide at room temperature,10 so the procedure described here allows ready access
to the corresponding pyrroles.
Scheme 2.
The method was then extended to afford the 3-alkyl pyrroles 4g–i (Table 1). The precursor
ketone 1g was prepared (80%) from the sodium salt of N-benzoylglycine (acetic anhydride/pyr-
idine to afford the oxazolone then aqueous reflux);11 1h was prepared (52%) from N-benzoyl-
glycine (1 equiv. BuLi then 3 equiv. EtMgBr, THF/ether, −78°C);12 1i was prepared (44%
overall), as shown in Scheme 3. These three approaches to the a-amidoketones 1 illustrate how
readily a variety of substituents R and R% can be introduced into the pyrrole ring using this
methodology.
Table 1
Entry
R
R%
Yield (%) for 1“3a
Yield (%) for 3“4a
a
b
c
d
e
f
g
h
i
CH3
CH3CH2
CH3
CH3CH2
CH3
CH3
CH3
CH3CH2
CH3(CH2)9
CH3
CH3
85
78
56
51
52
62b
69
65
59
93
72
79
78
70
61b
83
78
65
PhCH2
PhCH2
(CH3)2CH
CH3S(CH2)2
H
H
H
a For 3a–3e see Ref. 9; for 4a see Ref. 13; all other compounds were characterised by the usual analytical and
spectroscopic methods.
b R% is CH3S(CH2)2 in 1 but CH3SO2(CH2)2 in 3 and 4.

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Scheme 3.
Typical procedure for 3 to 4: The sulphone 3a (0.52 g, 1.5 mmol) was dissolved in dry THF
(20 cm3), and 1 M potassium tert-butoxide in tert-butanol (1.5 cm3, 1.5 mmol) was added. The
solution was refluxed for 2 hours, the THF was removed under reduced pressure and the residue
was partitioned between water and ethyl acetate. Flash chromatography (ethyl acetate–
petroleum spirit, 1:4) gave 4a13 as an oil (0.28 g, 93%); (found M+ 199.0985. C13H13NO requires
199.0997); lH (250 MHz; CDCl3) 2.06 (3H, s, CH3), 2.48 (3H, s, CH3), 6.02 (1H, d, J 3.3, pyrrole
H-4), 6.72 (1H, d, J 3.3, pyrrole H-5), 7.44–7.61 (3H, m, ArH), 7.72 (2H, m, ArH); lC (62.5
MHz; CDCl3) 11.2, 12.6, 113.6, 121.2, 122.1, 128.6, 129.9, 132.3, 135.1, 169.5.
It was expected that application of the method to a-amidoaldehydes would afford 2-
alkylpyrroles 5, but the intramolecular Wittig reaction took a different course. Thus the
aldehyde 6, obtained by oxidation of N-benzoylalaninol with DMSO/(COCl)2/Et3N, on treat-
ment with NaH followed by the 1-phenylthiovinyl triphenylphosphonium iodide gave, in 35%
yield, the cyclobutene 7, mp 119–121°C, lH (250 MHz; CDCl3) 1.65 (3H, s, CH3), 2.70 (1H, d,
J 12.5, CH), 2.90 (1H, d, J 12.5, CH), 6.05 (1H, s, CꢀCH), 6.75 (1H, br s, NH), 7.2–7.5 (8H,
m, ArH), 7.6–7.85 (2H, m, ArH). Apparently in changing from the ketone 1a to the aldehyde
6 as substrate, there is a change in the relative acidities of the NH proton and the a-H such that,
for 6, it is the a-H which is removed. It is worth noting that use of the N-Cbz protected
aldehyde 8 gave a complex mixture under the conditions of the intramolecular Wittig reaction
and no cyclised product was isolated (Scheme 4).
Scheme 4.
Acknowledgements
We thank EPSRC and Sittingbourne Research Centre for financial support (I.B.) for this
work.

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