Hydroacylation of α,β-unsaturated esters via aerobic C-H activation

Article abstract of DOI:10.1038/nchem.685

The development of methods for carbon-carbon bond formation under benign conditions is an ongoing challenge for the synthetic chemist. In recent years there has been considerable interest in using selective C-H activation as a direct route for generating reactive intermediates. In this article, we describe the use of aldehyde auto-oxidation as a simple, clean and effective method for C-H activation, resulting in the generation of an acyl radical. This acyl radical can be used for carbon-carbon bond formation and herein we describe the application of this method for the hydroacylation of α,β-unsaturated esters without the requirement of additional catalysts or reagents. This methodology generates unsymmetrical ketones, which have been shown to have broad use in organic synthesis.

Full text of DOI:10.1038/nchem.685

ARTICLES
PUBLISHED ONLINE: 6 JUNE 2010 | DOI: 10.1038/NCHEM.685
Hydroacylation of a,b-unsaturated esters via
aerobic C–H activation
Vijay Chudasama, Richard J. Fitzmaurice and Stephen Caddick
*
The development of methods for carbon–carbon bond formation under benign conditions is an ongoing challenge for the
synthetic chemist. In recent years there has been considerable interest in using selective C–H activation as a direct route
for generating reactive intermediates. In this article, we describe the use of aldehyde auto-oxidation as a simple, clean and
effective method for C–H activation, resulting in the generation of an acyl radical. This acyl radical can be used for carbon–
carbon bond formation and herein we describe the application of this method for the hydroacylation of a,b-unsaturated
esters without the requirement of additional catalysts or reagents. This methodology generates unsymmetrical ketones,
which have been shown to have broad use in organic synthesis.
he synthesis of complex organic frameworks using benign order to gain widespread use. In this paper, we report the realization
transformations continues to be a major challenge in of this goal and demonstrate that it is possible to intercept acyl rad-
1
T
organic synthesis . With increasing environmental concerns icals generated from aldehyde auto-oxidation with a,b-unsaturated
around energy efficiency and waste management, it is clear that syn- esters to generate 1,4-dicarbonyls. We believe that this represents a
thetic organic chemistry must continue to develop even more major breakthrough and highlights the powerful synthetic potential
powerful methods for the construction of complex molecules. of aldehyde auto-oxidation as an approach to C–H activation and as
Central to organic synthesis are methods for carbon–carbon bond a basis for carbon–carbon bond formation.
formation and in many cases the critical consideration is the
choice of an appropriate method for the selective generation of a Results
reactive intermediate from a neutral molecule. A common strategy We became interested in the pioneering work of Vinogradov who
is to prepare a modified substrate containing a functional group, reported the hydroacylation of dimethyl maleate 5 with butanal
which can then undergo a chemoselective reaction to generate the 1a to give ketone 6a by simply mixing the reagents at 21 8C
reactive intermediate of choice. An appealing alternative to the (ref. 27). However, it was found that this result was non-reproduci-
modified substrate/reagent approach is that of C–H activation. ble and we observed no consumption of 5 even with prolonged reac-
In particular, there have been significant developments in remote tion times. We concluded that in Vinogradov’s original work,
C–H activation processes in transition metal catalysis2–4
.
hydroacylation of alkene 5 was likely to have been catalysed by
Free-radical intermediates have played an important role in syn- low levels of cobalt not present in commercial aldehydes. Indeed,
thetic organic chemistry and such methods can offer a complementary
approach to the more vigorous conditions often required for two-
a
1
electron processes5–7. Although direct C–H activation has been used
O2
O
O
O
O
Initiation
in the field of radical chemistry there are significant problems with
O
R1
H
R1
R1
O
R1
OH
the selectivity of C–H abstraction8
–12
and more successful protocols
4
1
2
3
4
tend to use a modified substrate/reagent strategy, which can some-
times require noxious precursors and/or undesirable reagents ,13,14.
It is intriguing to note that the generally accepted mechanism for
the auto-oxidation of aldehyde 1 to carboxylic acid 4 invokes the
formation of an acyl radical 2, which is then intercepted by molecu-
lar oxygen. Decomposition of the resultant peracyl radical 3 to its
corresponding acid 4 with concomitant oxidation of additional
5
b
O
HO
O
O
1
1
a (R =n-Pr)
CO2Me
CO Me
CO Me
2
2
+
Air
,4-dioxane
CO2Me
CO Me
CO Me
1
2
2
5
6a
7a
1
5,16
aldehyde completes the auto-oxidation process (Fig. 1a)
.
c
1
We note that the auto-oxidation of aldehydes offers an interest-
ing opportunity for the mild and selective formation of acyl radicals
using only molecular oxygen as a reagent. The synthetic applications
of acyl radicals are well established13 and technologies exist for
1a (R =n-Pr)
O
Air
CO2Et
CO Et
2
1
,4-dioxane
4 days
17
18
radical-based hydroacylation using polarity reversal catalysis or
metals1 . However, there has been limited work on the synthetic Figure 1 | Auto-oxidation of aldehydes generates acyl radicals, which can
applications of aldehyde auto-oxidation22–24. We have become inter- be intercepted to generate carbon–carbon bonds. a, Aerobic auto-oxidation
ested in determining whether it is possible to generate new carbon– of aldehydes 1 in air proceeds via acyl radical 2 and peracyl radical 3 to give
carbon bonds via acyl radicals generated by aldehyde auto-oxidation carboxylic acid 4. b, Reaction of dimethyl maleate 5 with butanal 1a in
and have recently described the hydroacylation of vinyl sulfonates air generates the product of hydroacylation 6a and cyclic peroxide 7a.
and sulfones2 . However, despite this work, the scope of the c, Hydroacylation of crotonate 17 with butanal 1a gives 1,4-dicarbonyl 18.
class of alkene in this type of reaction needs to be extended in n-Pr, n-propyl.
7–21
5,26
Department of Chemistry, University College London, London WC1H 0AJ. *e-mail: s.caddick@ucl.ac.uk
5
92
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.685
ARTICLES
5
1
and 8 (Table 2). Hydroacylation of alkenes 5 and 8 with aldehydes
gave consistently good yields, which appear independent of alkene
Table 1 | Effect of concentration on hydroacylation of
dimethyl maleate 5 with butanal 1a in 1,4-dioxane at 60 8C.
geometry (Table 2, entry 8) and the nature of the ester (see
Supplementary Information). However, reaction of alkene 5 with
isobutyraldehyde 1b (Table 2, entry 2) only reached 55% consump-
tion of alkene owing to rapid oxidation of isobutyraldehyde 1b to its
23
†
†
†
Entry [5]* (mol dm
)
Conversion (%) Yield 6a (%) 6a:7a
1
5.00
2.00
1.00
0.50
0.33
0.25
0.20
0.33
50
60
85
100
100
100
100
77
37
35
50
64
77
74
70
40
1:0.34
2
3
4
5
6
7
1:0.22
1:0.07
1:0.05
1:0.04
1:0.03
1:0.03
1:0.78
26
corresponding carboxylic acid . As expected, at the elevated temp-
erature of 60 8C significant amounts of product 9 derived from de-
carbonylation were observed in hydroacylation of 1,2-diester alkenes
with secondary aldehydes 1b, 1e and 1f (Table 2, entries 2, 5 and 6).
This is consistent with a radical mechanism for the hydroacylation.
We then extended our method to 1,1-diesters and to this end we
studied the reactivity of alkene 10 with butanal 1a under aerobic oxi-
dation in 1,4-dioxane at 21 8C (Table 3). These initial studies gave
results that were consistent with those obtained for the 1,2-diesters
‡
8
Conditions: 5 (1 mmol), 1a (5 mmol), 1,4-dioxane, 60 8C.
†
*
Concentration refers to initial concentration of 5 in 1,4-dioxane before addition of 1a. Determined
by integration of 1H NMR relative to pentachlorobenzene as an internal standard at 100%
‡
consumption of butanal 1a. 1a (2 mmol).
5
and 8. As previously, heating to 60 8C suppressed formation of
addition of 1 mol% CoCl .6H O gave 100% conversion of alkene 5 cyclic peroxide 11 and encouraged formation of the desired hydro-
2
2
1
at 21 8C in 24 h, as determined by H NMR.
acylated product 14a. However, in contrast to the results obtained
We then sought to apply an aerobic protocol to the hydroacyla- for the 1,2-diester alkenes (Table 1), reactions were relatively unaf-
23
tion of alkene 5 (ref. 26). We were pleased to observe that when fected by concentration in the 0.2–5 mol dm range, with approxi-
treated with butanal 1a (5 equivalents) at 21 8C, and crucially in mately 10% variation in yield. Nonetheless, the highest yield
1
,4-dioxane, alkene 5 was hydroacylated to give ketone 6a, albeit observed for the hydroacylation of 10 with butanal 1a at 60 8C in
in a low yield (21%) and at low conversion (40%) after 6 days 1,4-dioxane was achieved at 1 mol dm (76%; Table 3, entry 1).
23
(Fig. 1b). In addition to the expected product of alkene hydroacyla-
With our optimized conditions for 1,1-diester alkenes we then
tion 6a we observed significant quantities of cyclic peroxide 7a (8%), examined the effect of aldehyde 1 on their hydroacylation
presumably derived via reaction of molecular oxygen with the (Table 3). We were pleased to find that uniformly good yields
adduct radical derived from acyl radical addition to 5 (see below).
were obtained for the hydroacylation of 10 with a range of alde-
In attempts to obviate the formation of cyclic peroxide 7a and hydes. However, the influence of steric hindrance on the reaction
improve the yield of the desired hydroacylation product 6a we outcome is displayed by the relatively modest yield obtained for
reasoned that exposure to air may have a significant impact on reaction of diethyl diester 10 with 2-ethylhexanal 1f (Table 3,
the reaction of alkene 5 with butanal 1a. We investigated the entry 5), with significant quantities of decarbonylated addition
effect of temperature and noted an increase in the 6a:7a ratio product observed (32%). In addition, very modest results were
and the yield of ketone 6a when the temperature was increased obtained for reactions with diester 12, especially with
from 21 8C to 60 8C (Table 1, entry 3). In addition, we examined
the effect of changing reaction concentration, and hence the
surface area:volume ratio, on the hydroacylation of alkene 5 with
Table 2 | Hydroacylation of 1,2-alkene diesters 5 and 8 with
butanal 1a (Table 1). The higher conversion and improved 6a:7a
aldehydes 1a–g.
ratio observed with decreasing concentration is presumably due to
more efficient trapping of the acyl radical 2 by alkene 5 than in
O
O
the reaction with molecular oxygen to give 3. Optimal conditions
R1
H
R1
1
R1
were established when the reaction was carried out at
CO Me
CO Me
CO Me
2
2
2
+
2
3
0.33 mol dm
(Table 1, entry 5), with more dilute regimes
CO Me
Air
CO Me
CO Me
2
2
2
1
,4-dioxane
proving detrimental to yield (Table 1, entries 6 and 7). Although
hydroacylation is feasible with 2 equivalents of aldehyde, albeit in
a reduced yield (Table 1, entry 8), the use of 5 equivalents ensures
a high yield of ketone 6a (Table 1, entry 5).
5 (Z ) or 8 (E )
6
9
Entry Alkene
Aldehyde
Yield*
6:9
(%)
CO Me
2
As previously reported, we found that hydroacylation of
alkene 5 with butanal 1a was completely suppressed by the addition
of radical inhibitor 2,6-bis(1,1-dimethylethyl)-4-methylphenol
1
1
CO Me
1a, R ¼
70
1:0
2
5
1
†‡
†
2
3
4
5
6
7
8
1b, R ¼
47
57
76
1:1.2
25
(
BHT) . Notably, hydroacylation of alkene 5 was equally effectively
carried out with reagent grade or freshly distilled aldehydes and in
glass or plastic vessels, suggesting that the process is readily repro-
ducible and does not require specific equipment. As anticipated, sig-
nificant polymerization was observed when using 5-hexenal in the
hydroacylation of alkene 5 or when using cyclohexene as the
solvent in the hydroacylation of 5 with butanal 1a. Of particular
note was the observation that the reaction was critically dependent
on molecular oxygen. When reactions were carried out under an
atmosphere of argon, we observed less than 5% conversion of
alkene 5 after 5 days. However, under an atmosphere of molecular
oxygen, reaction of alkene 5 with butanal 1a afforded no ketone
1
1c, R ¼
1:0
1
1d, R ¼
1:0
1
†
†
1e, R ¼
77
2.7:1
1
†
†
1f, R ¼
61
1.4:1
Et
1
1g, R ¼
60
64
1:0
5
MeO C
2
1
CO Me
2
1a, R ¼
1:0
6a, with only rapid conversion of butanal 1a to its corresponding
8
carboxylic acid observed.
The scope of this mild hydroacylation protocol was then explored
by examining the reaction of a selection of aldehydes 1, specifically
Conditions: alkene (1 mmol), 1 (5 mmol), 1,4-dioxane (3 ml), 60 8C, 3–10 days (see Supplementary
Information). *Overall isolated yield unless otherwise stated.
relative to pentachlorobenzene as an internal standard at 100% consumption of aldehyde 1. 55%
conversion of alkene 5.
†
Determined by integration of 1H NMR
‡
26
chosen owing to their varied auto-oxidation profiles , with alkenes
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.685
ARTICLES
Table 3 | Hydroacylation of 1,1-alkene diesters 10, 12 and 13 with aldehydes 1a–g.
O
CO Et
O
O
2
HO
R1
CO Et
2
1
CO Et
R3
2
R1
CO Et
+
2
CO Et
2
Air
R2 R3
CO Et
2
R2 R3
R2
1,4-dioxane
1
1
Entry
Alkene
CO2Et
Aldehyde
Product
Yield* (%)
1
2
3
1
CO2Et
1a
1c
1d
1e
1f
14a, R ¼
, R ¼ Me, R ¼ H
76
60
72
74
52
72
1
0
1
2
3
2
3
4
5
6
7
8
9
14c, R ¼
, R ¼ Me, R ¼ H
1
2
3
14d, R ¼
, R ¼ Me, R ¼ H
1
2
3
14e, R ¼
, R ¼ Me, R ¼ H
1
2
3
14f, R ¼
, R ¼ Me, R ¼ H
Et
1
2
3
1g
1a
1e
1a
1c
1d
1e
1f
14g, R ¼
, R ¼ Me, R ¼ H
5
CO2Et
CO Et
1
2
3
†
†
15a, R ¼
, R ¼ R ¼ Me
51 (57 )
2
12
1
2
3
†
15e, R ¼
, R ¼ R ¼ Me
2(10 )
CO2Et
CO2Et
1
2
3
†
16a, R ¼
, R ¼ OEt, R ¼ H
87
OEt
13
1
2
3
1
1
1
1
1
0
16c, R ¼
, R ¼ OEt, R ¼ H
85
87
1
2
3
1
16d, R ¼
, R ¼ OEt, R ¼ H
1
2
3
†
2
3
4
16e, R ¼
, R ¼ OEt, R ¼ H
24 (35 )
1
2
3
†
16f, R ¼
, R ¼ OEt, R ¼ H
2(20 )
Et
1
2
3
1g
16g, R ¼
, R ¼ OEt, R ¼ H
89
5
Conditions: alkene (1 mmol), 1 (5 mmol), 1,4-dioxane (see Supplementary Information), 60 8C, 3–7 days (see Supplementary Information). *Isolated yields unless otherwise stated. Values in parentheses
†
1
indicate conversion of alkene when not 100%. Determined by integration of H NMR relative to pentachlorobenzene as an internal standard at 100% consumption of aldehyde 1.
cyclohexanecarboxaldehyde 1e (Table 3, entries 7 and 8). In reac- transformation at 21 8C giving the desired hydroacylation product
tions involving diester 12 complete conversion of aldehyde to acid 16e in 54% isolated yield, at 70% conversion.
was observed in each case. It seems appropriate to conclude that
Most pleasingly, we have also extended the acceptor tolerance to
the superior yields observed for the 1,1-diesters in comparison to crotonate 17 (Fig. 1c). When we applied either of our prior opti-
the corresponding 1,2-diesters reflects the greater ability of the mized protocols, poor yields of ketoester 18 were observed
more electrophilic adduct radical to propagate the chain and/or (ꢀ20%). However, when using a larger excess of aldehyde (10
the more electrophilic nature of the alkene.
equivalents), a significantly improved yield was obtained.
In order to exemplify the mild nature of our aerobic alkene Although the yield is modest at 51%, it represents a major break-
hydroacylation protocol, we explored reactions with more challen- through in our methodology as it demonstrates applicability to
ging substrates. To this end, we investigated the hydroacylation of alkenes bearing a single ester substituent.
2-alkoxy-1,1-diester 13 (Table 3, entries 9–14) to give the corre-
sponding alkoxy-substituted 1,4 dicarbonyls 16a and 16c–g. We Discussion
were delighted to observe excellent yields for the hydroacylation There are a number of strategies that can be used for the hydroacy-
2
8,29
of 13 with primary aldehydes (Table 3, entries 9–11 and 14). It lation of alkenes, for example, Stetter reactions , rhodium cataly-
3
0,31
13,32
should be noted that, in contrast to the alkylated 1,1-diesters sis
or free radical reactions ; however, there are significant
1
0 and 12, no evidence for the formation of cyclic peroxide 11 limitations to these technologies. Specifically, toxic and/or expens-
2
3
(
R ¼ OEt, R ¼ H) was observed in reactions with 2-alkoxy ive reagents, often used in significant quantities, are required to
diester 13 when reactions were carried out at either 60 8C or 21 perform the role of activating one of the reacting partners with
C. The lower conversions observed for secondary aldehydes 1e the need for intricate reaction conditions. In the present case, we
8
and 1f (Table 3, entries 12 and 13) would appear to indicate that describe a simple method, which uses the two reacting partners
these reactions are also sensitive to steric hindrance. It is noteworthy and air, with no additional reagents, and we demonstrate the appli-
that hydroacylation of 13 may also be carried out at 21 8C, albeit, cation of this to a variety of alkenes.
in general, with slightly inferior yields (around 10% reduction)
We have considered both ionic and radical mechanisms for the
and significantly longer reaction times (approximately 5 days). hydroacylation of electron deficient alkenes under air and believe
However, the efficiency of hydroacylation of 13 with cyclohexane- that the dependence of the hydroacylation on molecular oxygen,
carboxaldehyde 1e was significantly improved by carrying out the inhibition of the hydroacylation by BHT and the formation of
5
94
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.685
ARTICLES
hydroacylation approaches17,18. Through careful control of reaction
conditions, particularly concentration and temperature, and hence
molecular oxygen exposure, we have achieved clean hydroacylation
without the need for additional reagents, which differentiates this
methodology from all other methods for hydroacylation. Although
other methods for the direct formation of acyl radicals from alde-
hydes are known and hydroacylation can be carried out using
O
R
O
R
R1
CO R
2
R1
H
H
CO2R
R
1
R
19
22
2
Initiation
1
1
7,35,36
thiols or other polarity reversal catalysts
, a combination of
CO
O
22
O
R
reagents is usually required, albeit under substoichiometric con-
ditions. We have shown that aldehyde auto-oxidation can be used
as a clean method for the site-selective generation of an acyl
radical and hence the hydroacylation of alkenes. Of particular
note is the hydroacylation of 2-alkoxy-1,1-diesters, which demon-
strates the mild nature of free radical chemistry as it has allowed
us to make products that would otherwise be challenging to syn-
thesize via ionic methodology. Moreover, the 1,4-dicarbonyls gener-
ated by this mild protocol offer opportunities for further synthetic
manipulation, and in particular, to gain access to functionalized
heterocyclic motifs. Thus we suggest that the ability to generate
acyl radicals by auto-oxidation has significant potential for
carbon–carbon bond formation and that this mode of reactivity
may have more generality than previously considered. It might
also be reasonable to assert that this method has the potential to
offer a valuable complement to other reagent-based methods for
C–H activation using metal or organic reagents. In the present
case, we simply use air as a reagent for the site selective generation
of carbon-centred radicals for carbon–carbon bond formation.
R1
R1
R1
CO R
2
25
2
R
2
3
2
2
O2
O2
O
R
O
O
R
O
R1
O
R1
CO R
R1
CO R
2
2
O
R
R
26
3
24
1
1
1
2
2
4
R
HO
R
O
O
R
O
R1
CO R
CO R
2
R1
2
H
OH
R
R
Methods
21
4
20
Representative procedure for the hydroacylation of a,b-unsaturated esters.
Aldehyde (5 mmol) was added to a solution of alkene (1 mmol) in 1,4-dioxane
(0.5–3 ml) and the reaction mixture stirred at 300 rpm at 60 8C in a stoppered
tube for the time specified as described in the Supplementary Information.
Note: reactions under the conditions stated are operated in a closed system above the
flash point of the solvent and appropriate safety measures should be implemented.
The solvent was removed in vacuo and purified by column chromatography to afford
the desired hydroacylation product. For spectral data for products see
Supplementary Information.
Figure 2 | Proposed mechanism for the aerobic hydroacylation of alkenes.
The fate of acyl radical 2 formed from aldehyde 1 is governed by its
propensity to react with alkene 22 to generate 23, to react with O to
2
generate peracyl radical 3 or to decarbonylate to form alkyl radical 25 at a
given reaction concentration. Radical 23 may react with additional aldehyde 1
to give ketone 19 or react with O to derive cyclic peroxide 20, presumably
2
via peroxy radical 24. Alkyl radical 25 can undergo radical addition to alkene
22 followed by abstraction from aldehyde 1 to generate 21 and regenerate 2.
Received 14 February 2010; accepted 21 April 2010;
published online 6 June 2010
4
, 19, 20 and 21 are overwhelmingly in favour of a radical mechan-
ism (Fig. 2).
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reaction stoichiometries that are comparable to many other
1
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We thank A.G. Davies and K.U. Ingold for helpful discussions. We gratefully acknowledge
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the EPSRC Mass Spectrometry Service for provision of mass spectra.
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Author contributions
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and analysed the data. V.C., R.J.F. and S.C. wrote the paper.
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Additional information
The authors declare no competing financial interests. Supplementary information and
chemical compound information accompany this paper at www.nature.com/
naturechemistry. Reprints and permission information is available online at http://npg.nature.
com/reprintsandpermissions/. Correspondence and requests for materials should be
addressed to S.C.
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4190–14191 (2009).
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