Two carbon homologated α,β-unsaturated aldehydes from alcohols using the in situ oxidation-Wittig reaction

Article abstract of DOI:10.1039/b306738f

The in situ oxidation-Wittig reaction, followed by subsequent hydrolysis, has been applied to the conversion of primary alcohols into α,β -unsaturated aldehydes. This conversion, which proceeds via the intermediacy of the homologated unsaturated dioxolanes, gives good to excellent yields with a range of benzylic alcohols and heterocyclic methanols.

Full text of DOI:10.1039/b306738f

Two carbon homologated a,b-unsaturated aldehydes from alcohols using
the in situ oxidation–Wittig reaction
Mark Reid,a David J. Roweb and Richard J. K. Taylor*a
a Department of Chemistry, University of York, Heslington, York, UK YO10 5DD. E-mail: rjkt1@york.ac.uk
b Oxford Chemicals, North Gare, Seaton Carew, Hartlepool, UK TS25 2DT
Received (in Cambridge, UK) 12th June 2003, Accepted 15th July 2003
First published as an Advance Article on the web 4th August 2003
The in situ oxidation–Wittig reaction, followed by sub-
sequent hydrolysis, has been applied to the conversion of
primary alcohols into a,b-unsaturated aldehydes. This
conversion, which proceeds via the intermediacy of the
homologated unsaturated dioxolanes, gives good to excellent
yields with a range of benzylic alcohols and heterocyclic
methanols.
Initial studies were carried out using benzyl alcohol and
phosphorane 3, generated in situ from the commercially
available dioxolanyl phosphonium bromide 4 (Table 1). Thus, a
one-pot MnO2 oxidation–Wittig reaction afforded the un-
saturated dioxolane intermediate 5a as an E–Z-mixture. A
variety of bases and solvent systems were screened. Use of
potassium tert-butoxide to facilitate the formation of phosphor-
ane 3 in situ, afforded only low yields of the desired acetal
(Table 1, entries i and ii). Similarly when phase transfer
conditions were employed (entry iii), a disappointing yield of 5a
was obtained.
a,b-Unsaturated aldehydes 1 are extremely important com-
pounds, particularly as synthetic intermediates1,2 and as fin-
ished products in the flavour and fragrance industry.3 Numerous
methods are available for their preparation1,2 although most
involve redox functional group transformations rather than
carbon–carbon bond formation. In principle, the directed aldol
approach devised by Trippett and Walker4 utilising a two
carbon homologation of the corresponding aldehyde with
formylmethylenetriphenylphosphorane 2 seems attractive (eqn.
1). However, the scope of this process is limited to more
reactive aldehydes5 (presumably due to the products 1 reacting
further), and it has not found widespread use. Cresp et al.
subsequently introduced the use of the related dioxolane reagent
3,5 generated in situ from phosphonium salt 4 and lithium
methoxide in methanol–DMF; the unsaturated dioxolane prod-
ucts were then readily hydrolysed and isomerised with aqueous
acid to afford a range of trans-a,b-unsaturated aldehydes.
Gratifyingly, however, the use of organic bases such as DBU
resulted in a marked increase in isolated yield (entry iv).
Furthermore, switching to the use of the bicyclic guanidine
base,
1-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene
(MTBD)6d,8 gave an excellent yield (86%) of acetal 5a after two
days at room temperature in DCM. Refluxing conditions were
then investigated in a range of solvents. We also established that
dilute hydrochloric acid could be employed to hydrolyse acetal
5 with concomitant Z–E-isomerisation. The optimum condi-
tions (entry vi) involved the use of refluxing THF overnight
followed by treatment with dilute hydrochloric acid giving an
excellent 82% overall yield of E-cinnamaldehyde.
Following these promising results, we proceeded to in-
vestigate the scope and limitations of the reaction in refluxing
THF, followed by direct hydrolysis, with a range of activated
alcohols (Table 2).9 Normal and electron deficient benzylic
alcohols gave good yields of the homologated unsaturated
(1)
Table 1 Conversion of benzyl alcohol into cinnamaldehyde 1aa
We have recently developed a number of one-pot transforma-
tions based on the manganese dioxide-mediated oxidation of
primary alcohols followed by in situ trapping of the resulting
aldehydes.6,7 This one-pot, tandem methodology, which re-
moves the need to isolate the intermediate aldehydes (a
particularly useful feature in the case of volatile, toxic or highly
reactive aldehydes), works well using a range of Wittig
reagents.6 Recently, we reported an oxidation-Wittig sequence
which converts alcohols into the two carbon homologated a,b-
unsaturated Weinreb amides which can be readily reduced to
afford a,b-unsaturated aldehydes.6f However, to the best of our
knowledge, there remains no general procedure for the direct
conversion of alcohols into a,b-unsaturated aldehydes. We
therefore investigated the extension of the in situ oxidation
methodology to the preparation of a,b-unsaturated aldehydes 1.
This communication outlines a new one pot MnO2 oxidation–
Wittig trapping sequence with subsequent hydrolysis to afford
a,b-unsaturated aldehydes 1 in good to excellent yield over the
three step sequence (eqn. 2).
Entry Base
Conditions
Product (%)
i
KOtBu (1.5 equiv.)
RT, 48 h
RT, 48 h
RT, 18 h
RT, 48 h
RT, 48 h
5a, 10
5a, 8
5a, 33
5a, 47
5a, 86
ii
KOtBu (2.2 equiv.)
K2CO3 + TDA-1b
DBU (2.2 equiv.)
MTBD (2.2 equiv.)
MTBD (2.2 equiv.)
MTBD (2.2 equiv.)
iii
iv
v
vi
vii
D, 17 h then 10% aq. HClc 1a, 82
RT, 3 d then SnCl2·2H2O
1a, 54
a With MnO2 (10 equiv.), salt 4 (1.6 equiv.), base (see above), 4 Å mol.
sieves and CH2Cl2 as solvent unless otherwise stated. b TDA-1 [tris(3,6-
dioxaheptyl)amine] was used in CH2Cl2–satd. aq. K2CO3. c THF as
solvent.
(2)
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Table 2 In situ oxidation-Wittig reaction then hydrolysis to give enals 1a
Reaction Isolated
Entry
i
Alcohol
Product
time/h
yield (%)
17
82
ii
9
80
Scheme 1
iii
iv
v
24
18
17
3.5
33
75
72
79
Wittig homologation–hydrolysis using the conditions reported
herein (4, MTBD, THF), to give good yields of E-enals as
shown in Scheme 1. This is noteworthy as Simoni et al. have
previously reported that enolisable aldehydes do not give good
yields of Wittig products on treatment with phosphonium salts
and guanidine bases, possibly due to competing aldol reac-
tions.8 We presume that phosphorane 3 must be particularly
efficient at trapping aliphatic aldehydes under the conditions
employed in the present study. Aldehydes 610 and 711 are
important flavour and fragrance chemicals,3 emphasizing the
value of this approach.
vi
viic
9
85
In summary, we have designed a practical, and in many cases,
high yielding synthesis of a,b-unsaturated aldehydes from
activated alcohols using an in situ MnO2 oxidation–Wittig
reaction followed by acidic hydrolysis. Work is now underway
to develop a true one-pot sequence in which the hydrolysis step
is carried out without the need for prior removal of the MnO2.
Applications of this methodology in natural product synthesis
are also being explored.
viii
ix
5.5
20
69
81
33
xe
23
We thank the EPSRC for a SOCSA Industrial CASE
studentship.
xi
16
46
43
12
Notes and references
xiif
1 For reviews see W. J. Ebenezer and P. Wight, Comprehensive Organic
Functional Group Transformations, Pergamon, Oxford, 1995, vol. 3,
Ch. 3.02, 53.
2 For recent publications in this area see G. Battistuzzi, S. Cacchi and G.
Fabrizi, Org. Lett., 2003, 5, 777; T. Suzuki, T. Makoto and Y.
Wakatsuki, Tetrahedron Lett., 2002, 43, 7531; P. K. Mahata, O. Barun,
H. Ila and H. Junjappa, Synlett, 2000, 1345; K. C. Nicolaou, Y.-L. Zhang
and P. S. Baran, J. Am. Chem. Soc., 2000, 122, 7596 and references
therein.
a Using manganese dioxide (10 equiv.), salt 4 (1.6 equiv.), MTBD (2.3
equiv.) and 4 A mol. sieves under nitrogen in refluxing THF for the
specified time followed by aq. HCl hydrolysis.9 b p-Methoxybenzaldehyde
was also isolated (ca. 50%). c Hydrolysis was unsuccessful-see text. d As a
mixture of isomers. e Refluxing dichloroethane as solvent. f Refluxing
toluene as solvent; hydrolysis was not attempted.
3 D. J. Rowe, Perfumer and Flavorist, 2000, 25, 1.
aldehydes 1a and 1b (entries i and ii). p-Methoxybenzyl alcohol
gave a lower yield of 1c (entry iii), presumably due to the lower
reactivity of p-methoxybenzaldehyde (which constituted the
main by-product of the reaction). We next moved on to
heterocyclic examples (entries iv-vii), and thiophene-3-metha-
nol, furan-2-methanol, and pyridine-3-methanol gave the ex-
pected E-enals 1d–f in good yields. In the case of pyridine-
2-methanol (entry vii), an excellent yield of the intermediate
dioxolane 5g was obtained but, using dilute hydrochloric acid or
Lewis acids, attempts to hydrolyse 5g to the corresponding
unsaturated aldehyde were unsuccessful.
Allylic and propargylic examples were also successful
(entries viii-xi), although the yields were reduced and solvent
optimization was often required. With decanol, however, the
dioxolane 5l was isolated in a paltry 12% yield after refluxing in
toluene for 46 hours (entry xii).
The results in Table 2 demonstrate the broad scope of this
oxidative methodology covering a structurally diverse group of
activated alcohols with many of the yields obtained being
comparable, or indeed better, than previously published homo-
logation reactions starting from the corresponding aldehydes.
Although decanol did not react efficiently using this
methodology, we have found that aliphatic aldehydes undergo
4 S. Trippett and D. M. Walker, J. Chem. Soc., 1961, 1266. For use in total
synthesis see R. Zamboni and J. Rokach, Tetrahedron Lett., 1982, 23,
4751; W. C. Still, C. Gennari, J. A. Noguez and D. A. Pearson, J. Am.
Chem. Soc., 1984, 106, 260.
5 T. M. Cresp, M. V. Sargent and P. Vogel, J. Chem. Soc., Perkin Trans.
1, 1974, 37. See also H. J. Bestmann, K. Roth and M. Ettlinger, Angew.
Chem., Int. Ed. Engl., 1979, 18, 687.
6 (a) X. Wei and R. J. K. Taylor, Tetrahedron Lett., 1998, 39, 3815; (b)
L. Blackburn, X. Wei and R. J. K. Taylor, Chem. Commun., 1999, 1337;
(c) X. Wei and R. J. K. Taylor, J. Org. Chem., 2000, 65, 616; (d) L.
Blackburn, C. Pei and R. J. K. Taylor, Synlett, 2002, 215; (e) K. A
Runcie and R. J. K. Taylor, Chem. Commun., 2002, 974; (f) L.
Blackburn, H. Kanno and R. J. K. Taylor, Tetrahedron Lett., 2003, 44,
115.
7 L. Blackburn and R. J. K. Taylor, Org. Lett., 2001, 3, 1637; H. Kanno
and R. J. K. Taylor, Tetrahedron Lett., 2002, 43, 7337; H. Kanno and R.
J. K. Taylor, Synlett, 2002, 1287; G. D. McAllister, C. D. Wilfred and
R. J. K. Taylor, Synlett, 2002, 1291; J. S. Foot, H. Kanno, G. M. P.
Giblin and R. J. K. Taylor, Synlett, 2002, 1293.
8 D. Simoni, M. Rossi, R. Rondanin, A. Mazzani, R. Baruchello, C.
Malagutti, M. Roberti and F. P. Indiviata, Org. Lett., 2000, 2, 3766.
9 Known products gave data consistent with those published; novel
compounds were fully characterised.
10 K. Anjou and E. von Sydow, Acta Chem. Scand., 1967, 21, 945.
11 E. Elkik, Bull. Soc. Chim. Fr., 1968, 283.
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