In situ alcohol oxidation - Wittig reactions using N-methoxy-N-methyl-2-(triphenylphosphoranylidine)acetamide: Application to the synthesis of a novel analogue of 5-oxo-eicosatetraenoic acid

Article abstract of DOI:10.1016/S0040-4039(02)02498-X

Benzylic, allylic, propargylic and unactivated alcohols can be oxidised with activated manganese dioxide in the presence of N-methoxy-N-methyl-2-(triphenylphosphoranylidine)acetamide to generate directly the corresponding α,β-unsaturated Weinreb amides. Elaboration of the resulting Weinreb amides is also described, in particular as part of a new route to analogues of the arachidonic acid metabolite 5-oxo-6E,8Z,11Z,14Z-eicosatetraenoic acid.

Full text of DOI:10.1016/S0040-4039(02)02498-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 115–118
In situ alcohol oxidation–Wittig reactions using
N-methoxy-N-methyl-2-(triphenylphosphoranylidine)acetamide:
application to the synthesis of a novel analogue of
5-oxo-eicosatetraenoic acid
Leonie Blackburn, Hisashi Kanno and Richard J. K. Taylor*
Department of Chemistry, University of York, Heslington, York YO10 5DD, UK
Received 24 September 2002; accepted 1 November 2002
Abstract—Benzylic, allylic, propargylic and unactivated alcohols can be oxidised with activated manganese dioxide in the presence
of N-methoxy-N-methyl-2-(triphenylphosphoranylidine)acetamide to generate directly the corresponding a,b-unsaturated Weinreb
amides. Elaboration of the resulting Weinreb amides is also described, in particular as part of a new route to analogues of the
arachidonic acid metabolite 5-oxo-6E,8Z,11Z,14Z-eicosatetraenoic acid. © 2002 Elsevier Science Ltd. All rights reserved.
We have recently described an in situ manganese diox-
ide-mediated alcohol oxidation-stabilised Wittig
sequence which can be applied to both activated1 and
non-activated2 primary alcohols (Eq. (1)), as well as to
1,2-glycols.3 We subsequently extended the oxidation–
Wittig methodology to allow the use of phosphonates
and non-stabilised phosphonium salts.4 This one-pot
methodology removes the need to isolate the interme-
diate aldehydes, and so is beneficial in terms of time
and particularly advantageous if the intermediate alde-
hydes are unstable, toxic or difficult to handle. In
order to further extend the scope of this process, and
to increase its utility in analogue synthesis, we decided
to investigate the use of the commercially available
stabilised Wittig reagent, N-methoxy-N-methyl-2-
(triphenylphosphoranylidine)acetamide (1).5 If success-
ful, we felt that the product Weinreb amides 2 would
be valuable for the preparation of a diverse range of
unsaturated aldehydes and ketones 3 (R%=H, alkyl,
aryl, Eq. (2)). This letter describes the success of this
methodology for a range of alcohols and also outlines
the elaboration of one amide adduct 2 into different
carbonyl derivatives 3. In addition, we report the
application of this new methodology to the prepara-
tion of a novel analogue of the bioactive arachidonic
acid metabolite 5-oxo-6E,8Z,11Z,14Z-eicosatetraenoic
acid.
We first set out to establish that phosphorane 1 was
compatible with manganese dioxide (Eq. (3)). Using
benzyl alcohol as substrate, we were delighted to
observe that the in situ manganese dioxide-mediated
alcohol oxidation-stabilised Wittig sequence proceeded
in dichloromethane at room temperature (RT) to give
product 2a in almost quantitative yield. The room
temperature reaction was rather slow but by carrying
out the reaction in dichloromethane at reflux, the trans-
formation was complete overnight.
(1)
(2)
* Corresponding author. E-mail: rjkt1@york.ac.uk
0040-4039/03/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02498-X

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L. Blackburn et al. / Tetrahedron Letters 44 (2003) 115–118
(3)
Table 1. MnO2 oxidation-stabilised Wittig reactions
a
Activated MnO2 (Aldrich, ca. 10 equiv.) was added to the alcohol and stabilised Wittig reagent (1.2 equiv.) in dichloromethane or toluene and
heated if required.
At reflux (21 h), a 53% yield was obtained (E,E:Z,E=12.5:1).
Trace amounts of the other two isomers were also observed.
At reflux (23 h), a 62% yield was obtained (2E,4Z:2Z,4Z:2E,4E:2Z,4E=7.7:1:1:trace).
b
c
d

L. Blackburn et al. / Tetrahedron Letters 44 (2003) 115–118
117
We next went on to explore the scope of the process
(Table 1).6,7 In addition to benzyl alcohol, substituted
analogues with electron-donating and electron-with-
drawing substituents could be employed, giving adducts
2b and 2c, respectively. 3-Phenylpropargyl alcohol and
cinnamyl alcohol also underwent the expected transfor-
mation in good yields giving 2d and 2e, respectively. In
all of these examples, the newly-formed alkene was
predominantly E- as expected.
to proceed at an acceptable rate, but the expected
products 2g and 2h were then obtained in reasonable
yields.
We next explored applications of the resulting Weinreb
amides (Schemes 1–3). Initially, we looked at the cin-
namyl derivative 2e and demonstrated that efficient
conversion to the corresponding aldehyde, phenyl
ketone and butyl ketone8 took place under standard
conditions, as shown in Scheme 1. Dienamide 2e was
used as the chromatographically pure E,E-isomer, and
the three adducts all retained this E,E-configuration.
We next examined reactions of E- and Z-hex-2-en-1-ol.
In both cases, when the reactions were carried out at
RT, the pre-existing alkene geometries were essentially
retained in adducts 2f. In refluxing dichloromethane,
Z-hex-2-en-1-ol underwent ca. 10% isomerisation,
however.
We then went on to utilise this methodology as the
cornerstone of a new approach (Scheme 2) to novel
analogues 7 of the bioactive arachidonic acid lipoxyge-
nase metabolite 5-oxo-6E,8Z,11Z,14Z-eicosatetraenoic
acid (5-oxo-ETE, 4).9,10 5-Oxo-ETE 4 is an important
mediator of inflammatory and allergic reactions,9,10 and
has attracted considerable recent synthetic attention.10
Finally, examples of semi-activated and unactivated
systems were examined. Both cyclopropylmethanol and
decanol required refluxing toluene for the conversions
Scheme 1.
Scheme 2.
Scheme 3.

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L. Blackburn et al. / Tetrahedron Letters 44 (2003) 115–118
In order to investigate the synthetic approach to 5-oxo-
ETE 4 shown in Scheme 2, we required trienol 5 for use
in the in situ manganese dioxide-mediated alcohol oxi-
dation-stabilised Wittig sequence. The complete
approach is illustrated in Scheme 3.
(L.B.) and to the Kureha Chemical Industry for a fully
funded studentship (H.K.). We would also like to thank
Dr. Xudong Wei for his interest in this research.
References
Triynol 11 has been described in the literature (as its
THP derivative),11 but we were attracted by a one-pot
preparation as shown in Scheme 3. Thus, a mixture of
hept-1-yne (8) and propargyl alcohol (10) were added
to a suspension of CuI, NaI and K2CO3 in DMF after
which 1,4-dichlorobut-2-yne (9) was added slowly.
After chromatography, the required product 11 was
obtained in 35–40% yield. Stereocontrolled reduction of
triyne 11 to give triene 5 was carried by treatment with
dicyclohexylborane followed by protonolysis. Triene 512
was obtained in 56% yield (as a single stereoisomer
according to 13C NMR spectroscopy).
1. (a) Wei, X.; Taylor, R. J. K. Tetrahedron Lett. 1998, 39,
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6. Novel products were fully characterised; known products
gave consistent spectroscopic data.
7. General procedure for the manganese dioxide process:
To a stirred solution of the alcohol (1 mmol) in CH2Cl2
or toluene (20 ml) was added N-methoxy-N-methyl-2-
(triphenylphosphoranylidine)acetamide (1, 1.2 mmol) fol-
lowed by activated MnO2 (Aldrich, 21764-6; 10 mmol)
and the reaction was stirred at the specified temperature.
After the specified time, the mixture was filtered through
Celite® washing with dichloromethane, and the volatiles
removed in vacuo. The products were then purified by
column chromatography.
8. As well as the 1,2-addition product (76%), the 1,4-adduct
was also obtained (14%).
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Powell, W. S.; Rokach, J. Tetrahedron Lett. 2000, 41,
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L.; Pivnitsky, K. K. Synthesis 1993, 65–66.
We next investigated the crucial in situ manganese
dioxide-mediated alcohol oxidation-stabilised Wittig
sequence using N-methoxy-N-methyl-2-(triphenylphos-
phoranylidine)acetamide (1) with trienol 5. We were
delighted to find that the process took place in reason-
able yield (59%) giving Weinreb amide 6 with the
original alkenes in the all-Z-configuration and the
newly formed alkene predominantly in the E-configura-
tion (E,Z,Z,Z:Z,Z,Z,Z=6.4:1), as established by high
1
field H NMR spectroscopy. In order to establish the
viability of Weinreb amide 6 as a versatile intermediate
for the preparation of 5-oxo-ETE analogues, we exam-
ined its reaction with n-butyllithium (Scheme 3). When
treated with n-butyllithium in THF at −78°C, amide 6
was cleanly transformed into the terminally reduced
5-oxo-ETE analogue 7, which was fully characterised.
It should be noted that the tetraene stereochemistry was
unaffected by the organometallic addition (and that no
1,4-addition was observed).
We are currently optimising the methodology described
in this paper, and also utilising the chemistry described
in Scheme 3 for the preparation of 5-oxo-ETE and
novel analogues.
Acknowledgements
12. Yadav, J. S.; Bhanu, L. R. M.; Dutta, D. Tetrahedron
1998, 54, 3929–3934.
We are grateful to the EPSRC for studentship funding