In situ alcohol oxidation-Wittig reactions using non-stabilised phosphoranes

Article abstract of DOI:10.1055/s-2002-19755

New procedures have been developed which allow the in situ alcohol oxidation-Wittig reaction using manganese dioxide to be employed with non-stabilised phosphoranes and stabilised phosphonate anions. A number of examples are described utilising benzylic, allylic and propargylic alcohols.

Full text of DOI:10.1055/s-2002-19755

LETTER
215
In Situ Alcohol Oxidation-Wittig Reactions Using Non-stabilised
Phosphoranes
In
situ Alcohol
e
O
xidation-
o
W
ittig React
nions ie Blackburn, Chengxin Pei, Richard J. K. Taylor*
Department of Chemistry, University of York, Heslington, York YO10 5DD, UK
Fax +44(1904)434523; E-mail: rjkt1@york.ac.uk
Received 1 November 2001
Table 1 In situ Oxidation-Wittig reactions using a Range of Bases
Abstract: New procedures have been developed which allow the in
situ alcohol oxidation-Wittig reaction using manganese dioxide to
be employed with non-stabilised phosphoranes and stabilised phos-
phonate anions. A number of examples are described utilising ben-
zylic, allylic and propargylic alcohols.
Key words: alkenes, Horner–Wadsworth–Emmons, oxidation, tan-
dem, Wittig
Base/solvent
K2CO3, MeOH
Triton B, THF
LiOH, THF
Yield 2 (%)
Base/solvent
DBU, THF
3, THF
Yield 2 (%)
0
0
20
We have recently reported the in situ alcohol oxidation-
Wittig reaction using manganese dioxide in the presence
of stabilised phosphoranes (Scheme).1 The initial studies
concentrated on activated alcohols but we subsequently
established that this procedure is also applicable to unac-
tivated primary alcohols.2 Other groups have reported
similar procedures utilising the Dess–Martin periodi-
nane,3 barium manganate4 and IBX5 as the oxidants. This
one-pot, tandem methodology obviates the need to isolate
the intermediate aldehydes, a particularly useful feature in
the case of aldehydes, which are volatile, toxic or highly
reactive.
0
3
PS-3,a THF
0
t-BuOK, THF
11
4, THF
34 (91)
aPS-3 = polymer supported-3
3
4
Initial studies were carried out using p-nitrobenzyl alco-
hol 1, methyl(triphenyl)phosphonium bromide and a
range of inorganic bases. Even after 3 days at room tem-
perature (r.t.), the best yield of p-nitrostyrene 2 was only
11% (t-BuOK, THF). We therefore turned to the use of
strong organic bases. DBU in THF gave an encouraging
yield (20%) and in view of Simoni’s results6 we were op-
timistic about the use of 1,5,7-triazabicyclo[4.4.0]dec-5-
Scheme
Herein we report the extension of the manganese dioxide ene 3. However, this reagent was totally ineffective as was
procedure to encompass the use of non-stabilised phos- its polymer supported variant. We were thus delighted to
phoranes and stabilised phosphonate anions.
find that 1-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene
(MTBD) 4 gave a 34% yield of alkene 2 under these stan-
dard conditions. Moreover, optimisation studies revealed
that the yield of 2 could be increased to 91% by the use of
pre-dried manganese dioxide in refluxing THF. The reac-
tions between a number of alcohols and phosphonium
salts were then investigated under these optimised condi-
tions (Table 2).7
The Wittig reaction using non-stabilised phosphonium
salts typically requires the use of anhydrous conditions
and relatively strong bases such as n-butyllithium. Re-
cently, however, Simoni et al. have shown that a number
of guanidines can promote in situ Wittig reactions be-
tween non-stabilised phosphonium salts and aldehydes.6
We have now demonstrated that Simoni’s conditions are
compatible with manganese dioxide oxidations (Table 1). With p-nitrobenzyl alcohol, we next examined its reaction
with benzyl(triphenyl)phosphonium chloride (entry ii).
This reaction proceeded efficiently and gave a slight pre-
dominance of the E-adduct, as would be expected from a
semi-stabilised phosphorane under these conditions. We
then moved on to the use of n-butyl(triphenyl)-phospho-
nium bromide with p-nitrobenzyl alcohol (entry iii). In
Synlett 2002, No. 2, 01 02 2001. Article Identifier:
1437-2096,E;2002,0,02,0215,0218,ftx,en;D25101st.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

216
L. Blackburn et al.
LETTER
this case we found that the yield of the in situ oxidation- E-cinnamyl alcohol underwent the in situ oxidation-
Wittig reaction could be improved (54% to 64%) by the Wittig reaction with complete retention of the pre-existing
addition of an equimolar amount of titanium isopro- double bond configuration whereas Z-hex-2-en-1-ol un-
poxide. The addition of titanium isopropoxide was uti- derwent some isomerisation. Attempts to extend this
lised in all of the other examples shown in Table 2 and in methodology to unactivated alcohols2 such as decanol
some cases gave dramatic improvements (see entry vi). It were unsuccessful.
should be noted that the reaction of 4-nitro- and 4-bro-
mobenzyl alcohols with n-butyl(triphenyl)phosphonium
bromide proceeded with Z-stereoselectivity (entries iii
and v), as expected.
Having successfully developed conditions for the in situ
alcohol oxidation-Wittig reaction with non-stabilised
phosphonium salts, attention was turned to the use of
phosphonates in these processes to effect in situ alcohol
oxidation-Horner–Wadsworth–Emmons (HWE) transfor-
mations. Initial studies involved treatment of p-nitroben-
zyl alcohol with manganese dioxide, triethyl
phosphonoacetate and a range of bases as shown in
Table 3.
Table 2 In situ Oxidation-Wittig Reactions using Guanidine 4
Entry
(i)
Alcohol
Conditionsa Product (yield)
Ph3PCH3Br
4 h
Table 3 In situ Oxidation-HWE Reactions using a Range of Bases
(91%)
(ii)
Ph3PCH2PhCl
12 h
(92%; Z:E = 4:5)
Base/conditions
Yield 5
(%)
Base/conditions
DBU, , 18 h
Yield 5
(%)
(iii)
Ph3PCH2PrBr
Ti(i-PrO)4,
24 h
LiOH, r.t., 4 d
LiOH, , 18 h
Et3N, , 18 h
61
75
24
57
(64%; Z:E = 4:1)b
DBU, LiCl, , 18 h 35
4, , 18 h 71 (81)
(iv)
(v)
Ph3PCH3Br
Ti(i-PrO)4,
48 h
(88%)
Lithium hydroxide has recently been used as a base for
phosphonate carbanion generation8 and under the in situ
manganese dioxide oxidation conditions with triethyl
phosphonoacetate, anhydrous LiOH gave ester 5 in 75%
yield when the reaction was carried out at reflux. Turning
to amine bases, triethylamine gave a disappointing yield
(24%) whereas DBU gave a 57% yield under the same
conditions. Somewhat surprisingly,9 the use of DBU/LiCl
gave a reduced yield (35%). Once again, however, the
best yield with an organic base was obtained using guani-
dine 4 (71%), and by using pre-dried manganese dioxide
the yield was improved still further (81%).
Ph3PCH2PrBr
Ti(i-PrO)4,
72 h
(64%; Z:E = 5:1)
(vi)
Ph3PCH3Br
Ti(i-PrO)4,
48 h
(61%)c
(vii)
(viii)
(ix)
Ph3PCH3Br
Ti(i-PrO)4,
48 h
(54%; E-only)
In view of the results outlined in Table 3, the use of lithi-
um hydroxide and guanidine 4 were explored with a num-
ber of activated alcohols and phosphonates (Table 4).
With triethyl phosphonoacetate, successful results were
obtained with both bases using a range of different benzyl
alcohols (entries i, iii and iv), as well as allylic (entries vi
and vii) and propargylic (entries viii and ix) systems. In
general, lithium hydroxide is the preferred base, although
in some cases guanidine 4 gives higher yields; both pro-
cess are rather slow, however.10 As seen from Table 4, it
is possible to form didehydroamino acid derivatives via
this in situ sequence (entry ii).
Ph3PCH2PhCl
Ti(i-PrO)4,
24 h
(55%; Z,E:Z,Z:E,E =
1.0:0.4:0.15)
Ph3PCH2PhCl
Ti(i-PrO)4,
24 h
(62%; Z:E = 1:2)
a Using pre-dried manganese dioxide (10 equiv) under nitrogen in re-
fluxing THF containing phosphonium salt (1.1 equiv), guanidine 4
(2.2 equiv) and in some cases Ti(i-PrO)4 (1 equiv).
b 54% without Ti(i-PrO)4.
c 25% after 3 d without Ti(i-PrO)4.
Pre-existing double bond geometry is retained (entries vi
and vii). It should be noted that the E-alkene products pre-
dominated using the standard conditions. However, use of
Ando’s phenoxy phosphonate11 (entry v) gave the Z-iso-
mer as the major product.
In addition to the benzylic alcohols, allylic and propargyl-
ic alcohols also reacted well under the in situ oxidation
Wittig conditions (entries vii–ix). It should be noted that
Synlett 2002, No. 2, 215–218 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
In situ Alcohol Oxidation-Wittig Reactions
Productb (yield)
217
Table 4 In situ Oxidation-HWE Reactions
Entry
(i)
Alcohol
Conditionsa
(EtO)2P(O)CH2CO2Et THF,
A: 12 h
B: 12 h
(A: 75%)
(B: 81%)
(ii)
NHZ
|
(MeO)2P(O)CHCO2Me
A: 48 h,
B: 6 h, r.t.
(A: 43%; > 95% Z)
(B: 49%; > 95% Z)
(iii)
(iv)
(EtO)2P(O)CHCO2Et THF,
A: 48 h
B: 72 h
(A: 43%)
(B: 70%)
(EtO)2P(O)CH2CO2Et THF,
A: 48 h
B: 48 h
(A: 69%)
(B: 53%)
(PhO)2P(O)CH2CO2Et THF,
A: 48 h
B: 48 h
(v)
(62%; Z:E = 2:1)
(vi)
(EtO)2P(O)CH2CO2Et THF, r.t.
B: 72 h
(A: 40%)
(B: 70%)
(vii)c
(viii)
(ix)
(EtO)2P(O)CH2CO2Et THF,
A: 72 h
(42%; > 95% Z,E)
(72%)
(EtO)2P(O)CH2CO2Et THF,
A: 24 h
(EtO)2P(O)CH2CO2Et THF,
A: 24 h
(66%)
a Using manganese dioxide (10 equiv) in refluxing THF containing phosphonate (1.2 equiv), guanidine 4 (2.2 equiv) or LiOH (2 equiv)/4Å
molecular sieves. The manganese dioxide was pre-dried (75 °C, overnight) for the MTBD (4) procedures. A = using LiOH; B = using base 4.
b > 95% E-isomer unless otherwise noted.
c Using pre-dried MnO2.
In conclusion we have successfully extended the in situ al- References
cohol oxidation-Wittig procedure using manganese diox-
ide to include non-stabilised phosphoranes and stabilised
(1) (a) Wei, X.; Taylor, R. J. K. Tetrahedron Lett. 1998, 39,
3815. (b) Wei, X.; Taylor, R. J. K. J. Org. Chem. 2000, 65,
phosphonate anions. Benzylic, allylic and propargylic al-
cohols have all been successfully employed in these pro-
cedures. Work is currently underway to further optimise
these procedures and to demonstrate their usefulness in
natural product synthesis.
617.
(2) Blackburn, L.; Wei, X.; Taylor, R. J. K. Chem. Commun.
1999, 1337.
(3) (a) Huang, C. C. J. Labelled Compd. Radiopharm. 1987, 24,
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Acknowledgement
We are grateful to the EPSRC for studentship funding (L. B.) and to
the China Scholarship Council for additional support (C. P.).
Synlett 2002, No. 2, 215–218 ISSN 0936-5214 © Thieme Stuttgart · New York

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L. Blackburn et al.
LETTER
column chromatography. Known products gave data
consistent with those published; novel compounds were
fully characterised.
(7) Manganese dioxide (activated, Aldrich 21, 764-6) was dried
in an oven overnight (ca. 75 °C). Dried manganese dioxide
(217 mg, 2.5 mmol) was then added to a solution of alcohol
(0.5 mmol), phosphonium salt (0.55 mmol), guanidine 4 (1.1
mmol) and Ti(i-PrO)4 (0.5 mmol, if specified in Table 2) in
THF (12 mL) which was heated to reflux under nitrogen. A
second portion of MnO2 (217 mg, 2.5 mmol) was added after
1 h and the reaction mixture heated at reflux for the time
stated. The reaction mixture was allowed to cool and then
filtered through Celite washing well with Et2O. The
(8) Bonadies, F.; Cardilli, A.; Lattanzi, A.; Orelli, L. R.; Scettri,
A. Tetrahedron Lett. 1994, 35, 3383.
(9) Blanchette, M. A.; Choy, W.; Davis, J. T.; Essenfeld, A. P.;
Masamune, S.; Roush, W. R.; Sakai, T. Tetrahedron Lett.
1984, 25, 2183.
(10) Addition of Ti(i-PrO)4 did appear to accelerate these
reactions but some transesterification was observed and the
procedure was not explored further. We were unable to
utilise unactivated alcohols such as decanol in this sequence.
(11) (a) Ando, K. Tetrahedron Lett. 1995, 36, 4105. (b) See
also: Ando, K. Synlett 2001, 1272; and references therein.
combined organic washings were neutralised with aq sat.
NH4Cl solution. The organic layer was separated and the aq
layer extracted with Et2O (3 15 mL). The combined
organic layers were dried (MgSO4), filtered and
concentrated in vacuo. The crude product was purified by
Synlett 2002, No. 2, 215–218 ISSN 0936-5214 © Thieme Stuttgart · New York