Unusual oxidation behaviour of a propargylic alcohol

Article abstract of DOI:10.1016/j.tetlet.2004.07.062

Attempts to convert a propargylic alcohol bearing an imidazolone substituent to the corresponding aldehyde under Parikh-Doering conditions gave an α,β-unsaturated-β-methylsulfanyl aldehyde, which cyclised under mildly acidic conditions. Attempts to convert a propargylic alcohol bearing an imidazolone substituent to the corresponding aldehyde under Parikh-Doering conditions gave an α,β-unsaturated-β- methylsulfanyl aldehyde, which cyclised under mildly acidic conditions.

Full text of DOI:10.1016/j.tetlet.2004.07.062

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 6541–6543
Unusual oxidation behaviour of a propargylic alcohol
a
b
b
Michael J. Porter,a, Nicola J. White, Garnet E. Howells and David D. P. Laffan
*
aDepartment of Chemistry, University College London, Christopher Ingold Building, 20 Gordon Street, London WC1H 0AJ, UK
bAstraZeneca, Charter Way, Silk Road Business Park, Cheshire, Macclesfield SK10 2NA, UK
Received 22 June 2004; accepted 14 July 2004
Abstract—Attempts to convert a propargylic alcohol bearing an imidazolone substituent to the corresponding aldehyde under
Parikh–Doering conditions gave an a,b-unsaturated-b-methylsulfanyl aldehyde, which cyclised under mildly acidic conditions.
ꢀ 2004 Elsevier Ltd. All rights reserved.
The marine sponge alkaloid agelastatin A (1), isolated in
1993,1 is one of a series of pyrrole–imidazole alkaloids,
which are biogenetically related to oroidin (2).2 The syn-
thetic interest shown in these alkaloids has culminated in
two total syntheses3a–d and one formal synthesis3e of 1;
model studies towards the core cyclopentane unit have
also been described (Fig. 1).3f
Our current investigations into a biogenetically-mod-
elled4 synthesis of 1 required the synthesis of alkynyl
aldehyde 6 (Scheme 1). While the corresponding propar-
gylic alcohol 5 could readily be prepared, oxidation of
the alcohol to the aldehyde gave some unexpected prod-
ucts, which are the subject of this communication.
Synthesis of 5 commenced from hydantoin (3), which
was selectively methylated at N-3 by reaction with dime-
thylacetamide dimethyl acetal.5 Subsequent addition of
the alkynyl Grignard reagent derived from TBS-pro-
Scheme 1. Reagents and conditions: (a) (i) MeC(OMe)2NMe2, tolu-
ene, reflux, 83%; (ii) tBuMe2SiOCH2C„CH, BuMgCl, THF; (iii)
TsOH, CHCl3, 62% (two steps); (b) (i) p-MeOC6H4CH2Cl, KOBut,
DMF, 87%; (ii) TBAF, THF, 99%.
tected propargyl alcohol, and elimination of the result-
ing tertiary alcohol afforded imidazolone
4
in
moderate yield.6,7 Protection of the remaining nitrogen
and removal of the TBS group led to the desired alcohol
5.
Initially, Parikh–Doering oxidation8 was employed in
an attempt to prepare aldehyde 6. On treatment of 5
with pyridine–sulfur trioxide and triethylamine in
DMSO, aldehyde 7 was formed, in which a methylsul-
fanyl substituent has been added to the b-position of
the desired ynal (Scheme 2).9 Aldehyde 7 was obtained
as a rapidly equilibrating 10:1 mixture of isomers, with
the (E)-isomer predominating.
Figure 1. Agelastatin A (1) and oroidin (2).
Keywords: Agelastatin; Oroidin; Imidazolone; Parikh–Doering oxida-
tion; Conjugate addition; Nazarov.
*
Corresponding author. Tel.: +44-20-7679-4710; fax: +44-20-7679-
7463; e-mail: m.j.porter@ucl.ac.uk
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.07.062

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M. J. Porter et al. / Tetrahedron Letters 45 (2004) 6541–6543
Scheme 4. Preparation and subsequent cleavage of 6.
Scheme 2. Attempted Parikh–Doering oxidation of 5.
Acknowledgements
We presume that under these conditions the desired
aldehyde 6 is initially formed, but is sufficiently reactive
towards soft nucleophiles that dimethyl sulfide adds at
the b-position to form sulfonium ion 8 (after proton-
ation of the allenolate). Removal of a methyl group by
one of the nucleophiles in the reaction mixture then
gives the observed product 7.
We thank EPSRC for funding (DTA award to N.J.W.),
and Dr. Abil Aliev for assistance with NMR spectro-
scopy.
References and notes
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Hoffmann, H.; Lindel, T. Synthesis 2003, 1753–
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Aldehyde 7 proved somewhat unstable to mildly acidic
conditions. On dissolution in CDCl3 was slowly con-
verted to bicyclic ketone 10 (Scheme 3),9 presumably
through protonation of the aldehyde, cyclisation to
bicyclic cation 9 (a process which could be considered
as either a nucleophilic attack of the imidazolone on
the protonated aldehyde, or a Nazarov cyclisation) fol-
lowed by loss of a proton and tautomerisation to afford
the observed product 10.
Oxidation of alcohol 5 to aldehyde 6 was successfully
achieved by treatment either with Dess–Martin period-
inane (DMP) followed by a sodium thiosulfate work-
up,10 or with barium manganate11 (Scheme 4). The
aldehyde 6 showed some instability to aqueous alkali,
and if a sodium hydroxide work-up10 was used following
DMP oxidation, terminal alkyne 11 was the only product
isolated, in 58% yield. Alternatively, aldehyde 6 could be
cleanly deformylated by treatment with 1.3M sodium
hydroxide solution in a two-phase reaction mixture.
In conclusion, some unexpected reactions have been
observed in attempts to oxidise the propargylic alcohol
5. Efforts are under way to discover whether these reac-
tions have any generality, and to complete a total syn-
thesis of 1.
9. Selected data: compound 7 (E-isomer): dH (400MHz,
C6D6): 9.42 (1H, d, J 7.4, CHO), 7.02 (2H, d, J 8.7,
2 · ArH), 6.66 (2H, d, J 8.7, 2 · ArH), 5.92 (1H, s,
Scheme 3. Acid-catalysed cyclisation of 7.

M. J. Porter et al. / Tetrahedron Letters 45 (2004) 6541–6543
6543
NCH@C), 5.85 (1H, d, J 7.4, C@CHCHO), 4.45 (2H, s,
CH2Ar), 3.23 (3H, s, OCH3), 2.96 (3H, s, NCH3), 1.44
(3H, s, SCH3); compound 10: dH (400MHz, CDCl3): 7.38
(2H, d, J 8.6, 2 · ArH), 6.79, 2H, d, J 8.6 (2 · ArH), 4.89
(1H, d, J 14.5) and 4.82 (1H, d, J 14.5, CH2Ar), 4.12 (1H,
dd, J 6.1, 1.3, CHSCH3), 3.73 (3H, s, OCH3), 3.37 (3H, s,
NCH3), 3.19 (1H, dd, J 18.1, 6.2) and 2.68 (1H, dd, J 18.1,
1.0, COCH2), 1.68 (3H, s, SCH3).
10. Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113,
7277–7287.
11. Firouzabadi, H.; Mostafavipoor, Z. Bull. Chem. Soc. Jpn.
1983, 56, 914–917.