Tandem oxidation-Wittig-Wittig sequences for the preparation of functionalised dienoates

Article abstract of DOI:10.1016/j.tetlet.2006.05.162

A range of functionalised dienes and trienes have been prepared by one-pot processes in which alcohol oxidation is accompanied by in situ Wittig homologation using Trippett's reagent [(triphenylphosphoranylidene)acetaldehyde] followed by addition of a sec

Full text of DOI:10.1016/j.tetlet.2006.05.162

Tetrahedron Letters 47 (2006) 5489–5492
Tandem oxidation–Wittig–Wittig sequences for the preparation
of functionalised dienoates
Stuart Lang and Richard J. K. Taylor*
Department of Chemistry, University of York, Heslington, York YO10 5DD, UK
Received 18 April 2006; accepted 24 May 2006
Abstract—A range of functionalised dienes and trienes have been prepared by one-pot processes in which alcohol oxidation is
accompanied by in situ Wittig homologation using Trippett’s reagent [(triphenylphosphoranylidene)acetaldehyde] followed by addi-
tion of a second stabilised phosphorane. This procedure has been applied to a-hydroxy carbonyl compounds and activated benzylic
alcohols.
ꢀ 2006 Elsevier Ltd. All rights reserved.
As part of a natural product study, we required easy ac-
cess to a range of oxygenated dienoates 1. Diethyl keto-
malonate 2 seemed a logical starting material and its
transformation could have been accomplished by a sin-
gle Wittig-type elaboration,1 or a stepwise sequence.
However, we were attracted by the possibility of carry-
ing out the one-pot tandem procedure shown in Scheme
1, as all of the starting materials are commercially avail-
able. Thus, the aim was to convert ketomalonate 2 into a
two/three carbon homologated aldehyde 5 using (triphen-
ylphosphoranylidene)acetaldehyde (Trippett’s reagent,
3), or its a-methyl analogue 4,2 and then to carry out
the second Wittig elaboration in situ to produce the tar-
get compounds 1. This approach obviously relies on the
fact that the conjugated aldehyde intermediate 5 is less
reactive than the original carbonyl substrate, but several
such examples were given by Trippett and Walker in
their original publication,2 and it seemed likely to be
the case when employing such a reactive carbonyl sub-
strate as a ketomalonate.
Therefore, the one-pot, tandem Wittig sequence using
diethyl ketomalonate 2 outlined in Scheme 1 was inves-
tigated and the results are gathered in Table 1.3 Using
(triphenylphosphoranylidene)acetaldehyde 3 as the ini-
tial Wittig reagent, followed by phosphoranes 6 or 7,
the expected adducts 1a and 1b4 were obtained in rea-
sonable, unoptimised isolated yields (entries i and ii).
When the methyl-substituted phosphorane 4 was em-
ployed in the first step, the reaction proceeded much
more slowly (24 h vs. 1 h) but the expected adduct 1c
was obtained, albeit in modest yield (entry iii).
We have recently described one-pot tandem oxida-
tion processes (TOP) in which manganese dioxide-
mediated alcohol oxidations have been combined with
O
O
O
O
O
O
(i) Ph P=C(R')CHO
3
EtO
OEt
(ii) Ph P=CHCOR
3
EtO
OEt
CHO
EtO
OEt
3, R' = H
4, R' = Me
6, R = OMe
7, R = Me
R'
O
R'
R
2
1
5
O
Scheme 1.
*
Corresponding author. E-mail: rjkt1@york.ac.uk
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.05.162

5490
S. Lang, R. J. K. Taylor / Tetrahedron Letters 47 (2006) 5489–5492
Table 1. Double Wittig elaboration of diethyl ketomalonate 2a
Entry
Phosphorane (i)
Phosphorane (ii)
Product
Isolated yield (%)
i
ii
iii
Ph3PCHCHO 3
Ph3PCHCHO 3
Ph3PC(Me)CHO 4
Ph3PCHCO2Me 6
Ph3PCHCOMe 7
Ph3PCHCO2Me 6
1a, R0 = H, R = OMe
1b, R0 = H, R = Me
1c, R0 = Me, R = OMe
82b
69b
54c
a In toluene at rt using 3 or 4 (1 equiv) followed by 6 or 7 (1.1 equiv); E-alkenes predominated (>95%).
b Both steps (i) and (ii) carried out for 1 h.
c Step (i) carried out for 24 h, step (ii) for 3 h.
phosphorane olefination.5 It was therefore of interest to
further elaborate the above procedure by incorporation
of an oxidative step (Scheme 2). Thus, alcohol 86 was
treated with MnO2 and Trippett’s reagent 3 followed
by phosphoranes 6 and 7 and we were pleased to find
that 1a7 and 1b were formed in reasonable isolated
yields (57% and 43%, respectively) via an oxidation–
Wittig–Wittig sequence.
The oxidation–double Wittig sequence with phosphor-
anes 3 and 6 was also carried out on the a-hydroxy ester,
ethyl glycolate 13 (Scheme 4). Using the conditions as
before, the expected dienoate 1411 was obtained, albeit
in low yield, along with the corresponding triene 15
(13%), which is formed by an oxidation–triple Wittig se-
quence (3 then 3 then 6). This reaction did not produce
other by-products and so the low yields may be due to
the volatility of the products.
In view of these results, we decided to explore the scope
of this process with more useful alcohol substrates. Ini-
tially, the one-pot oxidation–Wittig–Wittig sequence
was studied using a-hydroxyacetophenone 9 (Scheme
3). Oxidation in the presence of Trippett’s reagent 3
followed by addition of phosphorane 6 or 7 gave the
expected dienes 108 and 11.9,10 In a similar manner,
the use of the methyl-substituted phosphorane 4 in com-
bination with stabilised phosphorane 6 gave diene 12 in
64% yield, although as before in reactions involving 4, a
much longer reaction time was required compared to the
corresponding reaction involving 3 (24 h vs. 1 h). It is
also noteworthy that this initial Wittig reaction with 4
is not particularly stereoselective, with diene 12 being
isolated as a mixture of 2E,4E- and 2E,4Z-isomers (ca.
2:1).
The production of triene 15 encouraged us to explore
triene formation with other substrates. The most prom-
ising result was achieved using a-hydroxyacetophenone
with MnO2 and 2 equiv of Trippett’s reagent 3 in the
first step followed by treatment with phosphorane 6
(Scheme 4). This produced triene 1612 in 47% yield along
with diene 10 in 29% yield. Optimisation of this triene-
producing sequence should be straightforward.
Finally, preliminary investigations were carried out to
extend this methodology to benzylic alcohols and re-
lated systems (Scheme 5). These reactions were extre-
mely slow at room temperature and so, with 4-
nitrobenzyl alcohol 17a, various solvents were screened
at elevated temperatures. Thus, a mixture of alcohol
(i) MnO (10 equiv),
2
O
O
O
O
PhMe, r. t., 1 h
Ph P=CHCHO 3
1a, R = OMe, 57%
1b, R = Me, 43%
(>95% E)
3
EtO
OEt
EtO
OEt
(ii) Ph P=CHCOR, 1 h
3
OH
6, R = OMe
7, R = Me
8
R
O
Scheme 2.
(i) MnO (10 equiv),
2
O
O
PhMe, r. t., 1 h
10, R = OMe, 62%
11, R = Me, 43%
Ph P=CHCHO 3
3
OH
Ph
Ph
COR
(ii) Ph P=CHCOR 6 or 7
3
9
1 h
>95% E,E
(i) MnO (10 equiv),
2
O
O
PhMe, r. t., 24 h
12, 64%
Ph P=C(Me)CHO 4
2
4
3
OH
Ph
Ph
CO Me
2
(ii) Ph P=CHCO Me 6
3
2
9
1 h
2E,4E : 2E,4Z = 2:1
Scheme 3.

S. Lang, R. J. K. Taylor / Tetrahedron Letters 47 (2006) 5489–5492
5491
O
14, 30%
15, 13%
(i) MnO (10 equiv),
2
EtO
EtO
CO Me
O
2
PhMe, r. t., 1 h
Ph P=CHCHO 3
3
OH
+
O
EtO
(ii) Ph P=CHCO Me 6
3
2
13
1 h
CO Me
2
(>95% E,E and E,E,E)
O
O
(i) MnO (10 equiv),
2
O
16, 47%
10, 29%
Ph
Ph
PhMe, r. t., 3 h
CO Me
2
2 equiv Ph P=CHCHO 3
3
OH
+
Ph
(ii) Ph P=CHCO Me 6
3
2
9
2 h
(>95% E,E and E,E,E)
CO Me
2
Scheme 4.
O
(i) MnO (10 equiv),
2
THF, Δ, 24 h
Ph P=CHCHO 3
3
OMe
OH
Z
Z
(ii) Ph P=CHCO Me 6
3
2
Δ, 24 h
18a-d (> 95% E,E-)
17a-d
13
a, Z = 4-NO , 69%
2
b, Z = 2-NO , 67%
2
c, Z = 4-CO Me, 63%
2
14
d, Z= H, 25%
O
(i) MnO (10 equiv),
2
THF, Δ, 24 h
Ph P=CHCHO 3
3
OMe
OH
N
N
(ii) Ph P=CHCO Me 6
3
2
Δ, 24 h
19
20, 42% (> 95% E,E-)
Scheme 5.
17a, MnO2, and phosphorane 3 was heated in various
solvents for 24 h; phosphorane 6 was then added and
the mixture heated for a further 24 h. This study showed
that THF at reflux was optimum (yield of 18a,13 69%;
CH2Cl2, D, 54%; DMF, 100 ꢁC, 54%; PhMe, D, 34%).
rane. This procedure has been applied to a-hydroxy car-
bonyl compounds and activated benzylic alcohols.
Preliminary studies have been carried out in which an
oxidation–triple Wittig sequence has been used to pre-
pare functionalised trienes. We are currently optimising
these telescoped processes and investigating their appli-
cations in target molecule synthesis.
The low reactivity of phosphorane 3 leads to a limitation
of this procedure with benzylic alcohols; only those
which produce more reactive electron-defficient alde-
hyde intermediates undergo Wittig elaboration in rea-
sonable times. Thus, in addition to 4-nitrobenzyl
alcohol 17a, the 2-nitro- and 4-carbomethoxy- ana-
logues 17b and 17c and 2-pyridylmethanol 19, gave rea-
sonable yields of adducts (42–69%) whereas benzyl
alcohol itself produced diene 18d14 in only 25% yield.
Acknowledgements
We thank the EPSRC for postdoctoral support (S.L.).
References and notes
1. (a) Yamazaki, S.; Yamada, K.; Yamabe, S.; Yamamoto,
K. J. Org. Chem. 2002, 67, 2889–2901; (b) Volonterio, A.;
de Arellano, C. R.; Zanda, M. J. Org. Chem. 2005, 70,
2161–2170, and references therein.
2. Trippett, S.; Walker, D. M. J. Chem. Soc. 1961, 1266–
1272; For more recent applications of this phosphorane in
In summary, a range of functionalised dienes have been
prepared by one-pot processes in which alcohol oxida-
tion is accompanied by in situ Wittig homologation
using Trippett’s reagent 3, or its a-methyl derivative 4,
followed by addition of a second stabilised phospho-

5492
S. Lang, R. J. K. Taylor / Tetrahedron Letters 47 (2006) 5489–5492
processes with a subsequent Wittig elaboration see: Jones,
OCH3), 4.20–4.28 (4H, m, 2 · OCH2CH3), 6.23 (1H, d, J
15.2 Hz, RCH@CHCO2Me), 7.26 [1H, d, J 11.8 Hz,
(EtO2C)2C@CHR], 7.47 (1H, dd, J 15.2 Hz, 11.8 Hz,
RCH@CHCO2Me); dC (100 MHz, CDCl3) 14.0 (CH3),
14.1 (CH3), 52.1 (CH3), 61.9 (CH2), 61.9 (CH2), 130.8
(CH), 132.2 (C), 137.3 (CH), 139.7 (CH), 163.5 (C), 164.2
(C), 165.8 (C); m/z (CI) 274 (MNH4, 6%), 257 (MH, 100),
197 (8), 183 (6); HRMS (CI) [MH+], found 257.1030;
C12H17O6 requires 257.1025 (1.8 ppm error).
R. J.; Swaminathan, S.; Milligan, J. F.; Wadwani, S.;
Froehler, B. C.; Matteucci, M. D. J. Am. Chem. Soc. 1993,
115, 9816–9817; Lindel, T.; Franck, B. Tetrahedron Lett.
1995, 36, 9465–9468.
1
3. Novel compounds were characterised by IR, H and 13C
NMR spectroscopy, MS and HRMS.
4. Severin, T.; Ipach, I. Chem. Ber. 1978, 111, 692–697.
5. For a recent review see: Taylor, R. J. K.; Reid, M.; Foot,
J.; Raw, S. A. Acc. Chem. Res. 2005, 38, 851–869.
6. Nemoto, H.; Kubota, Y.; Yamamoto, Y. J. Org. Chem.
1990, 55, 4515–4516.
8. Allen, J. V.; Bergeron, S. S.; Griffiths, M. J.; Mukherjee,
S.; Roberts, S. M.; Williamson, N. M.; Wu, L. E. J. Chem.
Soc., Perkin Trans. 1 1998, 3171–3179.
7. Representative procedure: tandem oxidation–Wittig–Wit-
tig reaction to prepare dienoate 1a. A mixture of diethyl
hydroxymalonate 86 (176 mg, 1 mmol), (triphenylphos-
phoranylidine) acetaldehyde (304 mg, 1 mmol), activated
manganese dioxide (Aldrich 21764-6, 869 mg, 10 mmol)
9. Ong, C. W.; Chen, C. M.; Juang, S. S. J. Org. Chem. 1994,
59, 7915–7916.
10. An attempt was made to prepare diene 11 by mixing a-
hydroxacetophenone 9, MnO2, phosphorane 3 and phos-
phorane 7 in a single operation. However, very little (<5%)
11 was obtained with the major product being 5-phenyl-
pent-3-en-2,5-dione (48%); this presumably reflects the
greater reactivity of phosphorane 7 (or the lower solubility
of phosphorane 3).
11. Shieh, P. C.; Ong, C. W. Tetrahedron 2001, 57, 7303–7307.
12. Sakakiba, M.; Matsui, M. Agric. Biol. Chem. 1973, 37,
1131–1137.
˚
and powdered 4 A molecular sieves (1 g) in toluene (7 ml)
were stirred at room temperature for 1 h. After this time
methyl (triphenylphosphoranylidine) acetate (368 mg,
1.1 mmol) was added and the reaction stirred for a further
1 h. The mixture was then filtered through a pad of silica
and washed with diethyl ether (50 ml) and the solvent
removed in vacuo. The mixture was then purified by flash
chromatography on silica gel eluting with a petroleum
ether–ethyl acetate (4:1) mixture to give product 1a
(145 mg, 57%); mmax (film) 1721 cmꢀ1; dH (400 MHz,
CDCl3) 1.22–1.28 (6H, m, 2 · OCH2CH3), 3.71 (3H, s,
13. Banerji, A.; Banerjee, T.; Sengupta, R.; Sengupta, P.; Das,
C.; Sahu, A. J. Indian Chem. Soc. 2002, 79, 876–883.
14. Lewis, F. D.; Howard, D. K.; Barancyk, S. V.; Oxman,
J. D. J. Am. Chem. Soc. 1986, 108, 3016–3023.