Development of a robust reagent for the two-carbon homologation of aldehydes to (E)-α,β-unsaturated aldehydes in water

Article abstract of DOI:10.1039/c3gc41383g

Synthesis of a new pinacolacetal-phosphonium salt and its reaction with aldehydes to give homologated acetals and two-carbon homologated unsaturated aldehydes is presented. The chemistry takes place in water under mild conditions and the sequence can be performed in one-flask operation.

Full text of DOI:10.1039/c3gc41383g

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Development of a robust reagent for the two-carbon
homologation of aldehydes to (E)-α,β-unsaturated
aldehydes in water†
Cite this: Green Chem., 2013, 15, 3146
Received 11th July 2013,
Accepted 9th September 2013
DOI: 10.1039/c3gc41383g
James McNulty,* Carlos Zepeda-Velázquez and David McLeod
www.rsc.org/greenchem
Synthesis of a new pinacolacetal-phosphonium salt and its reac-
Several methods have been developed to achieve this trans-
tion with aldehydes to give homologated acetals and two-carbon formation in one or two steps using functionalised two-carbon
2
homologated unsaturated aldehydes is presented. The chemistry phosphonium salts or phosphonate derivatives. These
takes place in water under mild conditions and the sequence can reagents usually contain a masked carbonyl in the form of an
2
be performed in one-flask operation.
acetal. The reactions require the use of dry solvents and
strong bases (BuLi, NaNH , NaH etc.) and are problematic in
2
One and two-carbon carbonyl homologation reactions are
often employed as strategic transformations in organic syn-
thesis. Many methods exist for the one carbon homologation
of aldehydes to extended aldehydes or to the corresponding
2m
terms of partial acetal hydrolysis, which may occur under
2n
surprisingly mild conditions, as well as their low reactivity to
2l
some aldehydes and non-reactivity to enals. A new one-pot
reagent was developed by Wender et al. in relation to the syn-
1
carboxylic acid derivative (Fig. 1, process a). The conversion of
3a
thesis of the Bryostatin anticancer agents. This procedure
an aldehyde to the corresponding two-carbon homologated
unsaturated aldehyde (Fig. 1, process b) is a very desirable
transformation that is often employed in fine chemicals and
involves the metalation of (Z)-1-bromo-2-ethoxyethene at
−78 °C in THF using tBuLi and dimethylzinc before addition
of the aldehyde and subsequent acidic hydrolysis. Only one
2
,3
pharmaceutical syntheses.
The transformation is proble-
other application on the use of this reagent has been repor-
matic as the free alkenal cannot be present during the reaction
to avoid oligomerization, as such this transformation is typi-
cally carried out via a multistep process involving homologa-
tion to the unsaturated ester through a Horner–Wadsworth–
Emmons (HWE) or related Wittig process, DIBAL-H mediated
reduction to the allylic alcohol followed by Swern or Dess–
Martin oxidation leading to the homologated alkenal.
3b
ted. None of the reagents reported to date for this transform-
ation can been utilised in an aqueous environment.
The use of water as solvent in the synthesis of fine chemi-
cals and pharmaceuticals is highly desirable for environmental
and economic reasons and has been discussed in numerous
4
review articles. Our research group has been involved in the
development of Wittig-type olefination reactions in aqueous
media for several years, and we have highlighted the additional
advantages gained employing ylides derived from short-chain
5
trialkylphosphines. Ylides can be generated from these salts
under mild conditions, and these react with a wide range of
carbonyl compounds to deliver olefins with high (E)-stereo-
selectivity. Additionally, short chain trialkylphosphine oxides
are fully water soluble and can easily be removed using a
simple extraction protocol, in contrast to triarylphosphine
oxides, which are notoriously difficult to remove. In this com-
munication, we report the synthesis of a new pinacolacetal-
functionalised tripropyl phosphonium salt and its reaction
with aldehydes to give stable two-carbon homologated deriva-
tives as well as two methods for their hydrolysis, including a
one-pot operation, leading to the desired (E)-2-alkenals, in
water.
Fig. 1 Commonly employed one and two carbon homologation reactions.
Department of Chemistry & Chemical Biology, McMaster University,
1
280 main Street West, Hamilton, Ontario, Canada, L8S 4M1.
E-mail: jmcnult@mcmaster.ca; Tel: +1-905 525 9140 ext. 27393
Electronic supplementary information (ESI) available: Full experimental
†
1
13
31
The aldehyde-to-alkenal homologation has been described
using reagents such as A and B (Scheme 1) several times in the
procedures and characterisation data as well as copies of H, C and P NMR
spectra. See DOI: 10.1039/c3gc41383g
3
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Table 1 Two-carbon homologation of aldehydes to acetals and hydrolysis to
enals under aqueous Wittig conditions
Entry
1
Aldehyde
Time (h)
24
Yield 6
Yield 7
(E) : (Z)
a
87
95
>99 : 1
Scheme 1 A selection of previously described functionalised phosphonium
salts and synthesis of the new pinacolacetal salt 4.
a
2
3
4
24
24
24
91
89
90
93
>99 : 1
>99 : 1
>99 : 1
a
2
94
literature. Our initial work generating and trapping ylides
derived from salt C with aldehydes in water proved to be capri-
cious, resulting in formation of side products, which we attri-
buted to the instability of the acetal under the reaction
a
83
2
m,n
conditions. Bearing in mind the stability of cyclic acetals,
a
5
6
72
72
96
91
95
>99 : 1
95 : 5
and inspired by some of the recent chemistry documented for
6
stable functionalised pinacolboranes, we considered a func-
tionalised phosphonium salt of structural type D as a poten-
tially ideal trialkylphosphonium salt that would be chemically
robust and convey the advantages described above (E-stereo-
selectivity, allow generation and trapping of ylide in water and
provide ease of purification). To this end, the tripropylphos-
a
93
b
7
72
90
88
85 : 15
phine derived pinacolacetal phosphonium salt
4
was
synthesized from readily available 2-bromoacetaldehyde
diethylacetal 1 and acetone-pinacol 2 as shown in Scheme 1.
The intermediate bromoacetal 3 was prepared solvent-free and
purified by distillation in high yield and reacted with tripropyl-
phosphine, also under solvent-free conditions, to give the
novel phosphonium salt 4 a colourless hygroscopic solid in
high overall yield.
We next investigated the possibility of chemoselective olefin-
ation reaction of salt 4 under aqueous Wittig conditions
using 4-chlorobenzaldehyde 5a as the initial substrate. It was
determined that 5a reacted over 24 h with aqueous solutions
b
8
9
48
48
48
36
53
92
68
95 : 5
92 : 8
99 : 1
b
76
b
1
1
0
1
81
48
48
75
83
nd
nd
of 4 containing sodium hydroxide to produce the homologated 12
acetal 6a in 87% yield. Prior to considering a one-flask process
(
vide infra), the acetals were partitioned into ethyl acetate from
the aqueous phase at this stage, a process that also allows
clean separation of water-soluble tripropylphosphine oxide,
and isolated by filtration through a short silica-gel plug. The
reaction proved to be quite general for aromatic aldehydes 6a–
b
1
3
48
48
82
95 : 5
a
b
Hydrolysis with phosphoric acid. Hydrolysis with Amberlite resin.
6
g (Table 1, entries 1–7) and the corresponding acetals were
readily available in isolated yields of around 90%. The reaction
was also successful with unsaturated aldehydes leading to the yield. We now turned attention the hydrolysis of the stable
protected dienals 6h and 6i in moderate yields (entries 8 and 9). acetals 6a–m to allow access to the free α,β-unsaturated alde-
2
l
This process is reportedly challenging, but has been hydes 7a–m. Two methods were developed to allow for this
2
g,h
achieved under non-aqueous conditions.
Similarly, the new acetal hydrolysis under mild conditions, given the sensitivity
reagent allowed access to useful pyrene 6j and pyridine of the enal products. The use of dilute phosphoric acid (25% w/w)
analogs 6k and 6l (entries 10–12). The enolisable aliphatic was initially found to be satisfactory (Table 1, method a)
aldehyde 3-phenylpropanal was also investigated, a challen- and allowed slow hydrolysis of the acetals. This hydrolysis was
ging case given the possibility for aldol or Cannizarro side generally complete in 12 h at 65 °C from which process the iso-
reactions that may be anticipated in aqueous basic conditions. lation of the product enals 7a–7f was achieved in high yield
The protected acetal 6m was isolated in a reasonable 48% (Table 1, entries 1–6). The use of solid-supported acid catalysts
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can provide additional flow and/or process-chemistry advan- Swern (dry DMSO, oxalyl chloride, triethylamine) or Dess–
tages and we were delighted to find that use of Amberlite- Martin oxidation. Of the few methods developed to achieve
IR120 resin in its acidic hydrogen form also allowed for the slow, this transformation using functionalised two-carbon phos-
2
chemoselective hydrolysis of the pinacolacetals to the corres- phonium salts or phosphonate derivatives, the reactions
ponding α,β-unsaturated aldehydes in high isolated yields require the use of dry solvents and strong bases (BuLi, NaNH2,
(
Table 1, entries 7–10, 13). The unsaturated aldehydes were NaH etc.) and are problematic in terms of partial acetal hydro-
2
m
isolated by extraction into ethyl acetate and purification lysis. These reagents also generate an aqueous waste-stream
over a short silica gel column in each case. As we have noted containing phosphine oxide or phosphonate derivatives. The
previously concerning the use of ylides derived from trialkyl- new reagent 4 was designed taking advantage of the greater
5
phosphines, the unsaturated aldehydes are produced predo- stability of both cyclic acetals and pinacolacetal derivatives
minantly as the (E)-stereoisomer with high selectivity.
and proved to be most suitable for the homologation reaction
We next investigated the development of a one-flask, two under purely aqueous conditions. The reagent is produced in
stage operation for the overall aldehyde to enal homologation two steps under solvent free conditions and reacts with alde-
without isolation of the intermediate pinacolacetal, as shown hydes in water at 1.0 M concentration to deliver the protected
in Scheme 2. The initial olefination reaction was conducted as enals 6. The enals can be extracted into ethyl acetate sepa-
before using 4-bromobenzaldehyde 5b as test subject. Upon rating them from the aqueous waste-stream (containing tripropyl-
completion, dichloromethane was added to the flask and the phosphine oxide). Alternatively, a one-flask operation was
aqueous phase (containing salts and tripropylphosphine successfully implemented removing the aqueous waste from a
oxide) was removed from the flask. The dichloromethane solu- dichloromethane solution of the intermediate acetal. Hydro-
tion of the pinacolacetal was then directly treated with 25% lysis of the acetal intermediate also occurs in aqueous media
phosphoric acid solution and the hydrolysis reaction allowed containing phosphoric acid or acidic Amberlite resin, making
to proceed. Isolation and purification as before now delivered the hydrolysis step amenable to flow chemistry techniques.
the product enal in 93% overall yield, compared with 84% in Reagent 4 has been produced on a multi-gram scale (15 g at
the original two-flask process. Similarly, 4-methylbenzal- present) through a solvent-free procedure that is readily amen-
dehyde 5c and piperonal 5e were converted to the cinnamal- able to scale up. This reagent is the first such reagent that can
dehyde derivatives 7c and 7e also with greater efficiency be used to conduct the aldehyde to (E)-alkenal homologation
employing the one-flask process. The conversion of piperonal in a purely aqueous environment.
to methylenedioxy-cinnamaldehyde 7e serves as an important
In conclusion, we describe the synthesis of a novel pinacol-
example of the value of this one-flask aldehyde to enal conver- acetal phosphonium salt 4, which is readily available from
sion using the new salt 4. This aldehyde is a high value syn- inexpensive reagents 2-bromoacetaldehyde diethylacetal 1,
thetic intermediate and demonstrates the utility of this new acetone-pinacol 2 and tripropylphosphine. This salt allows
homologation process in converting commodity aldehydes to conversion of aldehydes to homologated acetals in good to
high value intermediates through a mild process under excellent yield under aqueous Wittig reaction conditions. Two
aqueous conditions. In addition to their uses in perfumery methods were developed for acetal hydrolysis under mild
and as flavouring agents, functionalised cinnamaldehydes aqueous conditions leading to the two-carbon homologated
such as 7e serve as valuable building block in organic syn- aldehydes in high yield and with high (E)-stereoselectivity. The
7
thesis and as substrates for organocatalytic transformations.
two steps can also be conducted in a one-flask operation
The conversion of an aldehyde to the corresponding which allows for a highly efficient overall transformation. The
-carbon homologated (E)-alkenal is a highly desirable trans- overall process appears very attractive for the conversion of
2
formation and is most often accomplished indirectly through commodity aromatic aldehydes to high-value functionalised
HWE and redox methodology using standard dry solvents, cinnamaldehyde derivatives. Further development of the
anhydrous bases and redox processes involving DIBAL-H and reagent 4 and application of the enals in organocatalytic pro-
cesses are under investigation.
Acknowledgements
We thank NSERC, CONACyT and Cytec Canada Inc for finan-
cial support of this work.
Notes and references
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(
Scheme 2 One-flask operation for the aldehyde to (E)-α,β-unsaturated alde-
hydes two-carbon homologation using reagent 4.
3
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