Manganese dioxide can oxidise unactivated alcohols under in situ oxidation-Wittig conditions

Article abstract of DOI:10.1039/a903980e

The in situ alcohol oxidation-Wittig reaction using manganese dioxide as the oxidant has been applied to semi-activated and, for the first time, unactivated alcohols to furnish the corresponding α,β-unsaturated esters.

Full text of DOI:10.1039/a903980e

Manganese dioxide can oxidise unactivated alcohols under in situ
oxidation–Wittig conditions
Leonie Blackburn, Xudong Wei and Richard J. K. Taylor*
Department of Chemistry, University of York, Heslington, York, UK YO10 5DD. E-mail: rjkt1@york.ac.uk
Received (in Liverpool, UK) 18th May 1999, Accepted 3rd June 1999
Table 1 In situ oxidation–Wittig reactions on ‘semi-activated’ alcoholsa
The in situ alcohol oxidation–Wittig reaction using man-
ganese dioxide as the oxidant has been applied to semi-
activated and, for the first time, unactivated alcohols to
furnish the corresponding a,b-unsaturated esters.
Substrate Product Solvent
t/h
Yield (%) Configuration
1
1
4
6
8
10
12
a
2
3
5
7
9
toluene
toluene
CHCl3
CHCl3
toluene
toluene
CHCl3
4
4
80
86
81
66
74
58
70
> 99% E
> 99% E
> 99% E
6+1 E+Z
3+1 E+Zb
> 95% Ec
> 95% Ed
Manganese dioxide is an extremely useful oxidant in organic
chemistry.1 Oxidations using manganese dioxide are partic-
ularly easy to perform as the oxidant is heterogeneous and the
reaction work-up usually involves simple filtration and evap-
oration of the solvent. An important use of manganese dioxide
is to convert primary alcohols into the corresponding aldehydes,
although the process is limited to activated systems of the
allylic/benzylic type. Recently, we described the development
of an in situ manganese dioxide oxidation–Wittig process in
which activated alcohols were treated with manganese dioxide
in the presence of a stabilised Wittig reagent: the resulting
aldehyde was trapped as it was formed to produce the
homologated a,b-unsaturated ester [eqn. (1)].2 This procedure
is particularly useful in cases where the intermediate aldehyde is
difficult to isolate (e.g. for reasons of volatility, toxicity,
liability to oligomerisation).
18
24
20
18
20
11
13
Activated MnO2 (Aldrich, ca. 10 equiv.) was added in three equal
portions to a mixture of the alcohol and the stabilised Wittig reagent,
Ph3PCHCO2R (1.2 equiv.), in the specified solvent which was heated under
20
reflux for the specified time. [a]D +40.5 (c 1, CHCl3); lit.,6 +38.3 (c 2,
b
CHCl3). [a]2D0 265.5 (c 1, CHCl3); lit.,7 265 (c 4.2, CH2Cl2). [a]2D0
227.9 (c 1.15, CHCl3).
c
d
In this same study (Table 1), we also investigated the
oxidation of alcohols containing a proximal heteroatom which
might activate the alcohol to oxidation inductively and/or by
providing a coordination site for the oxidant. Encouragingly,
tetrahydrofurfuryl alcohol 6 furnished the desired a,b-un-
saturated ester 7 in good yield. In contrast, oxidation of this
alcohol to the corresponding aldehyde is reported to be
problematic and at best yields of ca. 50% are obtained using
tetrapropylammonium perruthenate (TPAP) and 4-methylmor-
pholine N-oxide (NMO).5 The in situ reaction was also
successfully applied to several related enantiomerically pure
primary alcohols 8, 10 and 12. No racemisation was observed
according to polarimeteric measurements6,7 and good yields
were obtained. During the course of this study McKervey et al.
utilised our in situ oxidation–Wittig methodology to convert
non-racemic protected g-amino alcohols into the corresponding
a,b-unsaturated esters and ketones without loss of ster-
eochemical integrity.8
MnO2, CH2Cl2, room temp.
?
RCH2OH –––––––––––––––––––– RCHNCHE
(1)
Ph3PNCHE
R = vinyl, alkynyl, phenyl; E = CO2Et, etc.
Coincidentally, at around the same time, Barrett et al.
reported the combined use of the Dess–Martin periodinane and
stabilised phosphoranes,3 and Matsuda’s group employed
barium permanganate in a similar process.4†
The simplicity of the manganese dioxide procedure referred
to above, coupled with the toxicity of barium permanganate and
the sensitivity, and hazardous preparation, of the Dess–Martin
oxidant, prompted us to attempt to extend the scope of the
process (Tables 1 and 2). Initial studies concentrated on
alcohols which might be classified as ‘semi-activated’
(Table 1).‡ Thus, as expected, cyclopropylmethanol 1 under-
went smooth in situ oxidation–Wittig reaction giving enoates 2
and 3, as did the corresponding diol 4 producing dienoate 5.
In order to establish the limitations of this process we treated
a completely unactivated alcohol, decanol 14, under the in situ
manganese dioxide–Wittig conditions.
OH
CO2Me
CO2Et
1
2
3
CO2Et
CO2Et
CO2Et
CH3(CH2)8CH2OH
CH3(CH2)8
CH3(CH2)4
Ph(CH2)2
14
15
17
HO
OH
4
MeO2C
CO2Me
CH3(CH2)4CH2OH
5
16
CO2Et
CH2OH
Ph(CH2)3OH
OH
O
O
O
O
19
18
O
6
CO2Me
O
7
9
8
CO2Et
CO2Et
OH
OH
NBoc
NBoc
NBoc
NBoc
11
O
O
O
O
23
22
21
20
12
CH2OH
10
13
CO2Me
To our amazement (Table 2), enoate 159 was obtained in 80%
yield after 24 h reflux in toluene.§ This result was extremely
surprising given the generally accepted view that manganese
dioxide is not an effective oxidant for unactivated primary
alcohols.1 We therefore studied other unactivated primary
OH
CO2Me
Such reactions should prove useful in the synthesis of
cyclopropyl-based natural products.3a
Chem. Commun., 1999, 1337–1338
1337

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Table 2 In situ oxidation–Wittig reaction on unactivated alcoholsa
In summary, we have shown for the first time that unactivated
primary alcohols can be efficiently oxidised using manganese
dioxide under in situ Wittig conditions. Similar results are
reported with ‘semi-activated’ alcohols producing a range of
synthetically useful a,b-unsaturated esters.
Substrate Product Solvent
t/h
Yield(%)
Configuration
14
16
18
20
22
a
15
17
19
21
23
toluene
toluene
toluene
CHCl3
toluene
24
24
6
20
24
80
70
86
51
< 1
> 95% E
> 95% E
> 95% E
> 99% E
We thank the EPSRC for a research fellowship (X. W.) and
research studentship (L. B.). We are also grateful to Pfizer for
additional financial support and to A. D. Campbell for carrying
out the conversion of 12 into 13.
Activated MnO2 (Aldrich, ca. 10 equiv.) was added in three equal
portions to a mixture of the alcohol and the stabilised Wittig reagent,
Ph3PCHCO2R (1.2 equiv.), in the specified solvent which was heated under
reflux for the specified time.
Notes and references
† In preliminary studies, we have shown that chromium dioxide (Mag-
trieve™) can also be used for in situ oxidation–Wittig reactions.
‡ All new compounds were fully characterised spectroscopically and by
HRMS.
alcohols. Both hexanol 16 and 1-phenylpropan-3-ol 18 fur-
nished the desired products 17 and 19, respectively, in excellent
yield. With cyclohexylmethanol 20, the expected product 21
was obtained in reduced yield (51%); it seems likely that alkyl
substitution at the b-position relative to the alcohol is responsi-
ble for the reduction in efficiency. A limitation to the process
was realised when secondary alcohols were studied. As shown
in Table 2, treatment of cyclohexanol 22 under the in situ
oxidation–Wittig conditions gave only trace amounts of the
desired enoate 23. Similar results were also observed with
pentan-3-ol and dihydrocholesterol, which both failed to yield
the corresponding enoates. These results were not unexpected
as both the oxidation of secondary alcohols and the Wittig
reactions of stabilised phosphoranes with ketones are known to
be difficult compared with the corresponding sequence com-
mencing with primary alcohols.
We have carried out preliminary studies to try to rationalise
these results. The most important point is that on treatment with
manganese dioxide in the absence of a Wittig reagent, but under
otherwise identical conditions, the primary alcohols gave only
low yields of the corresponding aldehydes: for example, after
reflux in toluene with manganese dioxide for 24 h, decanol gave
decanal in only 12% yield, unreacted alcohol accounting for the
balance of material. One possible explanation for the high
conversions observed in the presence of the stabilised phosphor-
anes is that the primary alcohols are being converted into the
corresponding aldehydes in small equilibrium quantities with
the in situ Wittig reagent immediately trapping out the
aldehyde. Alternatively it is possible that the phosphorane may
be activating the oxidant or the alcohol (or the intermediate
complex) to oxidation. Further mechanistic studies are in
progress.¶
§ Representative procedure: Activated manganese dioxide (0.3 g) was
added to a stirred solution of decanol (158 mg, 1 mmol) and ethoxy-
carbonylmethylenetriphenylphosphorane (418 mg, 1.2 mmol) in toluene
(25 ml) and the mixture was heated to reflux. Two further portions of
manganese dioxide (ca. 0.3 g each) were added to the reaction over the first
hour and then it was stirred and heated until TLC indicated that reaction was
complete (ca. 24 h). The manganese dioxide was removed by filtration
through Celite, the Celite was washed well with toluene, and the combined
organic portions were concentrated in vacuo to ca. 1–2 ml. Column
chromatography (light petroleum–Et2O 5+1) gave ethyl trans-dodec-
2-enoate (181 mg, 80%) as a colourless oil with spectroscopic data
consistent with those published (ref. 9).
¶ Addition of Ph3PO or pyridine to the manganese dioxide oxidation of
decanol under toluene reflux (24 h) increases the yield from 12 to ca.
40%.
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Communication 9/03980E
1338
Chem. Commun., 1999, 1337–1338