Synthesis of γ-ketophosphonates via aerobic hydroacylation of vinyl phosphonates

Article abstract of DOI:10.1016/j.tetlet.2010.12.083

γ-Ketophosphonates are commonly employed as non-hydrolysable phosphate mimetics and as tools in synthesis. The synthesis of γ-ketophosphonates under mild conditions via interception of acyl radicals generated by aldehyde auto-oxidation is described.

Full text of DOI:10.1016/j.tetlet.2010.12.083

Tetrahedron Letters 52 (2011) 1067–1069
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Tetrahedron Letters
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Synthesis of
c-ketophosphonates via aerobic hydroacylation of vinyl
phosphonates
⇑
Vijay Chudasama, Jenna M. Ahern, Richard J. Fitzmaurice, Stephen Caddick
Department of Chemistry, University College London, London WC1H 0AJ, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
c
-Ketophosphonates are commonly employed as non-hydrolysable phosphate mimetics and as tools in
synthesis. The synthesis of -ketophosphonates under mild conditions via interception of acyl radicals
generated by aldehyde auto-oxidation is described.
Received 12 October 2010
Revised 7 December 2010
Accepted 17 December 2010
Available online 24 December 2010
c
Ó 2011 Elsevier Ltd. All rights reserved.
c
-Ketophosphonates, and their corresponding phosphonic
formation of aldehyde 4 and phosphonate 5. Consistent with previ-
ous studies, reaction between vinyl phosphonate 1 and butanal
(2a) was suppressed completely by addition of 2,6-di-tert-butyl-
4-methylphenol (BHT) (10 mol %), clearly indicative of a radical
mechanism for the hydroacylation of vinyl phosphonate 1.36
acids, have been established as useful tools in both synthetic
chemistry1–6 and in biology as non-hydrolysable phosphate
mimetics.7,8 For example,
c-ketophosphonates have been success-
fully employed as non-hydrolysable mimetics for dihydroxyace-
tone phosphate,9 as inhibitors of phosphoglycerate kinase10 and
as b-lactamase inhibitors.11
Although alternative methods have been developed for the
preparation of
c
-ketophosphonates,12–16 the most commonly
employed approach is based around conjugate addition to an
enone.6,17,18 In recent years, the development of catalytic methods
to prepare unsymmetrical ketones via the hydroacylation of
alkenes has received a great deal of attention.19,20 In addition,
the formation of unsymmetrical ketones via acyl radical mediated
carbon–carbon bond formation has been widely investigated.21–29
However, radical approaches often require noxious precursors or
chain carriers that are toxic and/or complicate the purification of
reaction products.30,31 Although alternative methods have been
developed for radical alkene hydroacylation, they have not been
widely employed.32,33
Scheme 1. Hydroacylation of vinyl phosphonate 1 with butanal (2a).
Recently, we described methods for the hydroacylation of elec-
tron-deficient alkenes bearing sulfonate, sulfone and ester substit-
uents with simple alkyl aldehydes via interception of the acyl
radicals generated during aldehyde auto-oxidation.34–36 Herein,
we report the application of this approach to the synthesis of
Table 1
Optimisation of the reaction of vinyl phosphonate 1 with butanal (2a)a
Entry
T (°C)
[1]b (mol dm-1
)
% Conv. 1
3a:4:5c
Yield 3ad (%)
1
2
3
4
5
6
7
8
20
40
60
60
60
60
60
80
1.00
1.00
5.00
2.00
1.00
0.50
0.25
1.00
15
60
—
—
<5
35
61
67
70
60
55
69
c-ketophosphonates via the aerobic hydroacylation of vinyl phos-
100
100
100
100
100
100
1:0.27:0.07
1:0.19:0.08
1:0.18:0.09
1:0.16:0.10
1:0.10:0.14
—
phonates with both simple and, notably, functionalised aldehydes.
We began investigations focusing on the hydroacylation of
dimethyl vinyl phosphonate (1) with butanal (2a) (5 equiv) in
1,4-dioxane at 20 °C, and were pleased to observe formation of
c
-ketophosphonate 3a, albeit in very low yield, <5% by 1H NMR
a
at 15% conversion of 1, after 144 h (Scheme 1). In addition, careful
Conditions: 1 (1 mmol), 2a (5 mmol), 1,4-dioxane (see Table 1), 24 h.
Concentration of 1 refers to initial concentration of 1 in 1,4-dioxane before the
examination of the crude 1H NMR spectrum indicated the
b
addition of 2.
c
Determined by integration of the 1H NMR spectrum relative to pentachloro-
⇑
Corresponding author.
E-mail addresses: VPEnterprise@ucl.ac.uk, s.caddick@ucl.ac.uk (S. Caddick).
benzene as an internal standard.
d
Isolated yield.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.12.083

1068
V. Chudasama et al. / Tetrahedron Letters 52 (2011) 1067–1069
Table 2
Despite the low yield for the hydroacylation of vinyl phos-
Aldehyde scope in the hydroacylation of vinyl phosphonatesa
phonate 1 with butanal (2a) (Scheme 1), we were sufficiently
encouraged to embark upon an optimisation study focusing on
temperature and concentration to attempt to control exposure of
the reaction to molecular oxygen, hence to ameliorate formation
of aldehyde 4 and phosphonate 5 (Table 1). Gratifyingly, increasing
the reaction temperature had a marked impact on the yield of
ketophosphonate 3a with the optimal yield, 70%, afforded at
60 °C and a concentration of 1.00 mol dmÀ3 (Table 1, entry 5);
heating to higher temperatures did not affect the yield significantly
(Table 1, entry 8). We attribute the improved yield of ketophosph-
onate 3a to the lower concentration of dissolved molecular oxygen
at elevated temperatures promoting acyl radical trapping by vinyl
phosphonate 1 in preference to molecular oxygen. This is sup-
ported by the lower conversions of vinyl phosphonate 1 observed
at lower temperatures (Table 1, entries 1 and 2) compared to those
achieved at 60 and 80 °C (Table 1, entries 5 and 8).
Entry
Product
Yield (%)b
70
1
2
3
4
68c
72
65
5
6
71
74
The lower yields observed for the hydroacylation of vinyl phos-
phonate 1 with butanal (2a) at higher (Table 1, entries 3 and 4) and
lower concentrations (Table 1, entries 6 and 7) than the optimal
1.00 mol dmÀ3 could be rationalised by the increased formation
of aldehyde 4 and phosphonate 5, respectively (Scheme 2). We
anticipate that aldehyde 4 is formed from reaction of peracyl rad-
ical 6, formed during the auto-oxidation of aldehyde 2a to its cor-
responding acid 7, with vinyl phosphonate 1 via peracyl ester 9.
Thus, at high surface area:volume ratio, that is, high reaction con-
centrations (Table 1, entries 3 and 4), increased exposure to air
promotes trapping of acyl radical 8 by molecular oxygen to give
a peracyl radical 6, and hence aldehyde 4, rather than vinyl phos-
phonate 3a, thus lowering the yield of ketophosphonate 3a and
decreasing the 3a:4 ratio. Although the formation of aldehyde 4
is suppressed at low reaction concentrations (Table 1, entries 6
and 7), unsurprisingly, an increased 3a:5 ratio was observed due
to reaction of vinyl phosphonate 1 with the solvent; consequently
lowering the yield of ketophosphonate 3a.
7
8
9
68
62d
67
10
57
11
12
13
14
60
20d
0
68
We then sought to evaluate aldehyde scope in the hydroacyla-
tion of vinyl phosphonate 1. Hence, we selected aldehydes with a
range of auto-oxidation rates13 and aldehydes bearing a range of
functional groups to emphasise the mild nature of the reaction
conditions (Table 2). To our delight, hydroacylation of vinyl phos-
phonate 1 under optimised conditions (Table 1, entry 5) was
shown to be tolerant of aldehydes bearing acetal, alcohol, aryl,
epoxide and ester functionalities (Table 2, entries 5–9); exemplify-
ing the mild, orthogonal nature of our reaction conditions. Also
encouraging was the success of cyclopropyl- and cyclohexyl-carb-
oxaldehydes (Table 2, entries 10 and 11) as well as b-branched
aldehydes (Table 2, entries 4, 6, 8 and 14). Consistent with a radical
mechanism was the poor tolerance of our methodology to alde-
hydes bearing alkenes (Table 2, entries 12 and 13). Although reac-
tion of vinyl phosphonate 1 with b-citronellal proceeded with 100%
conversion of vinyl phosphonate 1 (Table 2, entry 13), no clear evi-
dence for the formation of the corresponding hydroacylation prod-
uct 3m or other low molecular weight products resulting from
radical addition to vinyl phosphonate 1 was apparent, presumably
due to polymerisation under the reaction conditions. However, the
15
16
17
0e
0
60d,f
a
b
c
Conditions: 1 (1 mmol), 2 (5 mmol), 1,4-dioxane (1 mL), 60 °C, 24 h.
Isolated yield unless otherwise stated.
10 equiv of acetaldehyde used.
Determined by integration of the 1H NMR spectrum relative to pentachloro-
d
benzene as an internal standard.
e
Dimethyl (3,3-dimethylbutyl)phosphonate isolated in 46% yield.
80% conversion of diethyl E-1-propenylphosphonate.
f
corresponding reduced aldehyde could be employed successfully
to afford 3n in good yield (Table 2, entry 14). Upon reaction of vinyl
phosphonate 1 with pivaldehyde (2o) none of the desired keto-
phosphonate 3o could be isolated. However, dimethyl (3,3-dim-
ethylbutyl)phosphonate, corresponding to the addition of a tert-
butyl radical to 1, was isolated in 46% yield (Table 2, entry 15). In-
deed, complete decarbonylation of pivaldehyde and trapping of the
intermediate tert-butyl radical with 1 could be achieved in a 68%
yield at 100 °C.
We then took the opportunity to explore the efficiency of
b-substituted vinyl phosphonates in aerobic hydroacylation.
Unfortunately, although reaction of -methyl vinyl phosphonate
with butanal (2a) proceeded with 100% conversion of the vinyl
phosphonate in 16 h, none of the desired -ketophosphonate 10
a- and
a
Scheme 2. Proposed mechanism for the formation of aldehyde 4.
c

V. Chudasama et al. / Tetrahedron Letters 52 (2011) 1067–1069
1069
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