Metal-free, hydroacylation of CC and NN bonds via aerobic C-H activation of aldehydes, and reaction of the products thereof

Article abstract of DOI:10.1039/c3ob41632a

In this report, a thorough evaluation of the use of aerobically initiated, metal-free hydroacylation of various CC and NN acceptor molecules with a wide range of aldehydes is presented. The aerobic-activation conditions that have been developed are in sharp contrast to previous conditions for hydroacylation, which tend to use transition metals, peroxides that require thermal or photochemical degradation, or N-heterocyclic carbenes. The mildness of the conditions enables a number of reactions involving sensitive reaction partners and, perhaps most significantly, allows for α-functionalised chiral aldehydes to undergo radical-based hydroacylation with complete retention of optical purity. We also demonstrate how the resulting hydroacylation products can be transformed into other useful intermediates, such as γ-keto- sulfonamides, sultams, sultones, cyclic N-sulfonyl imines and amides.

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ARTICLE TYPE
Metal-free, hydroacylation of C=C and N=N bonds via aerobic C-H
activation of aldehydes, and reaction of the products thereof
Vijay Chudasama, Ahmed R. Akhbar, Karim A. Bahou, Richard J. Fitzmaurice and Stephen Caddick*
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
In this report, a thorough evaluation of the use of aerobically initiated, metal-free hydroacylation of
various C=C and N=N acceptor molecules with a wide range of aldehydes is presented. The aerobic-
activation conditions that have been developed are in sharp contrast to previous conditions for
hydroacylation, which tend to use transition metals, peroxides that require thermal or photochemical
10 degradation, or N-heterocyclic carbenes. The mildness of the conditions enables a number of reactions
involving sensitive reaction partners and, perhaps most significantly, allows for α-functionalised chiral
aldehydes to undergo radical-based hydroacylation with complete retention of optical purity. We also
demonstrate how the resulting hydroacylation products can be transformed into other useful
intermediates, such as γ-keto-sulfonamides, sultams, sultones, cyclic N-sulfonyl imines and amides.
Although direct C-H activation has been used in the field of
radical chemistry there are often significant problems with the
selectivity of C-H abstraction,5-7 and the more successful
protocols tend to use a modified substrate/reagent strategy.
45 Moreover, a significant number of the most widely used methods
employ expensive, toxic and environmentally damaging reagents
or catalysts, and/or large excesses of noxious reagents or
solvents.5-11 Nonetheless, it should still be appreciated that free
radical processes have played an important role in synthetic
50 organic chemistry and such methods can offer a complementary
approach to the more vigorous conditions often required for two
electron processes.5,12
In view of the limitations of current strategies toward radical-
based C-H activation, we became interested in developing an
55 alternative. Upon examination of the generally accepted
mechanism for the auto-oxidation of aldehydes to carboxylic
acids, we were intrigued to note that it evokes the formation of an
acyl radical 6 from an aldehyde 5 via the action of molecular
oxygen (Scheme 1).13 In this pathway, the acyl radical 6 reacts
60 with molecular oxygen to form peracyl radical 7, which then
abstracts an H-atom from another molecule of aldehyde
regenerating acyl radical 6. The resultant peroxyacid 8 then reacts
with another molecule of aldehyde to afford 9, which undergoes
decomposition to yield two molecules of carboxylic acid 10.13
15 Introduction
The development of methods to construct new chemical bonds
efficiently in a selective manner whilst minimising energy usage
and production of waste has, arguably, never been of greater
importance.1 Thus, the synthesis of complex molecules using
20 environmentally benign transformations has become a major
focus in organic synthesis.1 Despite recent work on the
development of more efficient chemical processes, it is still the
case that numerous synthetic transformations are inherently
limited as they employ a multi-step mode of reactivity, i.e. where
25 a starting material 1 is converted to a desired product 4 via a
number of intermediates, 2 and 3 (Figure 1).2 Such an approach
depends on: A) the ease of introduction of a precursor functional
group into a starting material (1) to give intermediate 2, B) ease
of precursor (2) conversion into an active species (3), and C)
30 selectivity and efficiency of the reaction of the active species to
produce the desired product (4). Each step in the process
introduces inefficiencies that multiply through the multi-step
conversion and typically involve the use of additional reagents,
which results in increased waste production. An appealing
35 alternative to the modified substrate/reagent approach is that of
C-H activation.2,3 In particular, in recent years, there have been
significant developments in remote C-H activation processes
using transition metal catalysis.4
40
Fig. 1 Strategies for bond formation
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NMR integration after 2 h. A simple set of aldehydes 5a-j, a
functionally diverse series of aldehydes 5k-t, aromatic aldehydes
40 5u-w, and enantiopure aldehydes 5x-y were all evaluated under
the reaction conditions.
Table 1 Auto-oxidation of aldehyde 5 to acid 10
Scheme 1 Aldehyde auto-oxidation pathway
Entry
Aldehyde 5
5a
5:10a
Although the synthetic applications of acyl radicals are well
established8 and technologies exist for radical based
hydroacylation using polarity reversal catalysis or metals,14-18
there has been limited work on the synthetic applications of
aldehyde auto-oxidation.8,19-21 We have recently described the
radical hydroacylation of vinyl sulfonates, sulfones and
phosphonates, α,β-unsaturated esters and azo-dicarboxylates
1
1:0.37
5
2
1:1.04
5b
5c
3
4
1:0.39
1:0.27
5d
5e
10 using acyl radicals generated via the aldehyde auto-oxidation
pathway.22-26 Efficient C-C and C-N bond formation was
achieved under benign conditions by the trapping of acyl radicals
(6) generated from aldehydes (5) with radical acceptors (11) to
initiate a chain reaction process, leading to the formation of
15 hydroacylation product 13 (Scheme 2). We also described some
of the utility of the derived hydroacylation products 13 in a range
of further transformations.24,26
5
6
1:0.34
1:0.50
5f
5g
7
8
1:0.04
1:1.54
5h
9
1:0.99
5i
10
1:0.00b
5j
11
12
1:0.32
1:0.40
5k
Scheme 2 Mechanism for aerobically initiated hydroacylation
20
Herein, we report a thorough evaluation of the use of
aerobically initiated hydroacylation with a wide range of
aldehydes and double bond acceptor molecules. In our analysis,
we examine aldehyde functional group tolerance with the various
acceptors and the significance of the rate of aldehyde auto-
25 oxidation on yield. Further evidence for the radical nature of the
pathway is also provided. In addition, a series of methods by
which the hydroacylation products can be transformed into other
useful intermediates, such as γ-keto-sulfonamides, sultams,
sultones, cyclic N-sulfonyl imines and amides, are also described.
5l
13
14
1:0.17
1:0.12
5m
5n
5o
15
16
17
1:0.25
1:0.14
1:0.40
5p
30 Results and Discussion
5q
5r
Aerobic auto-oxidation of aldehydes to carboxylic acids
18
19
1:0.44
Central to our methodology is the aerobic C-H activation of
aldehydes. Thus, we sought to explore the rate at which different
aldehydes auto-oxidise to their corresponding carboxylic acids
35 (Table 1). To achieve this, a fixed volume of each aldehyde (500
µL) was stirred in the same shaped vessel at the same stirring rate
1:0.00b
5s
20
1:0.00b
5t
1
(300 rpm) and the ratio of aldehyde 5 to acid 10 assessed by H
2
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THF
PhMe
DMF
MeOH
H2O
64
71
82
12
100
28
25
30
4
21
1:0.34
5u
78
35 Conditions: n-butanal 5a (5 mmol) and vinyl sulfonate 14 (1 mmol) were
stirred at 300 rpm in solvent (1 mL) at 21°C for 24 h.
22
23
1:0.32
1:0.02
5v
Hydroacylation was most readily affected in ethereal-based
solvents such as 1,4-dioxane and ethylene glycol dimethyl ether,
and perhaps most significantly, on H2O. Although the highest
40 yield observed for the hydroacylation of 14 with 5a was on H2O,
further optimisation of the reaction conditions for our
hydroacylation protocol was also continued for 1,4-dioxane as
solvent, since the use of H2O would preclude the use of solid
aldehydes. It should also be noted that, in all solvents, addition of
45 radical inhibitor bis(1,1-dimethylethyl)-4-methylphenol (BHT),
suppressed reaction significantly.
5w
24
25
1:0.12
5x
1:0.00c
5y
Conditions: aldehyde 5 (500 µL) stirred at 300 rpm at 21°C for 2 h unless
otherwise stated. a Ratio of aldehyde 5 to acid 10 after 2 h stirring of
aldehyde 5 (500 µL) at 300 rpm determined through comparison of the 1H
NMR integration of aldehyde 5 and acid 10. It should also be noted that
5 not stirring, significantly reduced the rate of auto-oxidation. As certain
aldehydes were contaminated with a minor amount of acid, the ratios
quoted are relative to the initial ratio of aldehyde to acid (where
applicable). b No conversion of aldehyde observed, even after 24 h. c 32%
Conversion of aldehyde but no corresponding acid formation observed by
10 integration of 1H NMR relative to pentachlorobenzene as an internal
standard.
Following our study on the effect of varying solvent we
proceeded to explore the effect of aldehyde stoichiometry on
yield. To do this, aldehyde stoichiometry was varied between 1
50 and 10 equivalent(s) for hydroacylation of 14 with 5a on H2O and
in 1,4-dioxane (Table 3).
Table 3 Hydroacylation of vinyl sulfonate 14 with aldehyde 5a with
various equivalents of aldehyde 5a
Although it has recently been reported that certain aldehydes
(i.e. fragrant aldehydes) auto-oxidise at a rate that is partially
dependent on their structure,27 there does not appear to be any
15 obvious relationship between structure of aldehyde and rate of
auto-oxidation in the series evaluated in this study. In fact, we
observed that aldehydes bearing even minor structural changes
brought about significant differences in the rate of acid formation
(see Table 1, Entries 2 and 24; and 4 and 7). Interestingly, certain
20 aldehydes did not undergo any conversion, even after prolonged
reaction times of 24 h (Table 1, Entries 10, 19 and 20). Although
aldehyde 5y did undergo appreciable conversion, 32%, it was
converted to acetaldehyde and acetic acid rather than its
corresponding acid 10y (Table 1, Entry 25).
Conversion
Solvent
5a/eq.
Yield 15a/%a 15a:16ab
14/%
100
100
100
95
1,4-Dioxane
10
5
4
3
2
1
10
5
4
3
64
65
57
50
37
26
80
77
79
78
78
47
1:0.12
1:0.13
1:0.16
1:0.20
1:0.27
1:0.40
1:0.04
1:0.04
1:0.03
1:0.04
1:0.05
1:0.14
75
52
H2O
100
100
100
100
100
75
25 Hydroacylation of pentafluorophenyl vinyl sulfonate (PFP)
Studies toward developing an aerobically initiated
hydroacylation protocol began with the hydroacylation of vinyl
sulfonate 14, which has previously been shown to be an excellent
radical acceptor.28 A structurally simple aldehyde that has a mid-
30 range oxidation rate (see Table 1), n-butanal 5a, was chosen as
the aldehyde component. Initially a screen of solvents was carried
out to determine the optimum solvent (Table 2).
2
1
Conditions: n-butanal 5a and vinyl sulfonate 14 (1 mmol) on H2O or in
55 1,4-dioxane were stirred at 300 rpm for 24 h. a Determined by integration
of 1H NMR relative to pentachlorobenzene as an internal standard.
b Determined by 1H NMR integration.
In 1,4-dioxane, maximum yield of ketone 15a was observed
with 5 equivalents of aldehyde, whereas on H2O there was no
60 vast improvement in yield when using greater than 2 equivalents
of aldehyde. As such, the use of 5 equivalents of aldehyde in
1,4-dioxane, and 2 equivalents of aldehyde on H2O were chosen
as the optimal stoichiometries to proceed with. The major
limitation on yield where fewer equivalents of aldehyde were
65 employed was the increased formation of double addition product
16a.
Table 2 Hydroacylation of vinyl sulfonate 14 with aldehyde 5a in various
solvents
Solvent
1,4-Dioxane
Et2O
Conversion of 14/%
Yield 15a/%
100
40
82
65
13
39
64
We next sought to evaluate reaction time by determining yield
of ketone 15a for the hydroacylation of 14 with 5a in the H2O
and 1,4-dioxane conditions at 0.5, 1, 2, 3, 4, 6, 8, 16 and 24 h
CH2Cl2
CH3OCH2CH2OCH3
100
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(Table 4). It was determined that the optimal reaction times in the
1:0.54
-
74
83
47
69
1,4-dioxane and H2O conditions were 1 h and 3 h, respectively,
with longer reactions having no significant effect on yield.
5e
Table 4 Hydroacylation of vinyl sulfonate 14 with aldehyde 5a after
5 various times
1:0.03b
0.05
5f
5g
1:0.12b
1:4.85
0.02
-
62
54
0 (0)
37 (60)
5h
Solvent
Time/h
Yield 15a/%a
1:0.01b
-
-
54 (75)
0 (0)
5 (80)
0 (0)
1,4-Dioxane
0.5
1
2
3
4
6
8
16
24
0.5
1
2
3
4
6
8
16
24
49
65
64
65
63
65
65
66
64
60
70
75
78
79
82
79
80
81
5i
1:0.03b
5j
Conditions for reactions in 1,4-dioxane: n-butanal 5a (5 mmol) and vinyl
25 sulfonate 14 (1 mmol) were stirred at 300 rpm in 1,4-dioxane (1 mL) at
21°C for the time specified in the ESI. Conditions for reactions on H2O:
n-butanal 5a (2 mmol) and vinyl sulfonate 14 (1 mmol) were stirred at
300 rpm in H2O (1 mL) at 21°C for the time specified in the ESI. a Ratio
determined by 1H NMR integration in D2O. b Due to poor solubility of
30 aldehyde in D2O, a DMSO/D2O (1:1) mixture was used. c Solubility of
aldehyde in H2O at 30 °C. d All reaction proceeded with 100% conversion
of 14 unless otherwise stated in parenthesis.
H2O
In both the 1,4-dioxane and water conditions, moderate to
good yields of ketone were observed across the series with the
35 exception of aldehydes 5b, 5h and 5j. The absence of any strong
correlation between yield of ketone and the extent of hydration
and/or solubility, except in exceptional circumstances (e.g.
acetaldehyde 5h), was particularly pleasing as it showed that
these parameters are fairly insignificant for efficient
40 hydroacylation to transpire on water.
The moderate yields observed for the hydroacylation of
isobutyraldehyde 5b was attributed to the propensity of this
aldehyde to undergo auto-oxidation rapidly, therefore resulting in
poor trapping of its corresponding acyl radical by alkene 14. This
45 hypothesis is supported by the sub-optimal conversion of alkene
14 and complete conversion of aldehyde under the reaction
conditions. A similar rationale may also be applied to explain the
low yield of ketone 15h observed on application of aldehyde 5h
in the 1,4-dioxane conditions. Interestingly, in the water-based
50 conditions, the attempted hydroacylation of acetaldehyde 5h
afforded no ketone and gave no alkene conversion with complete
conversion of aldehyde. This result can, however, be rationalised
in that acetaldehyde is completely soluble in water31 and is also
known to readily react with water to form a hydrate. These
55 characteristics of acetaldehyde thus prevent hydroacylation from
ensuing when using water as solvent.
Aldehyde 5j, which did not appear to auto-oxidise in our
previous study (see Table 1), underwent no conversion in both
reaction conditions (even after 72 h), and therefore resulted in 0%
60 conversion of vinyl sulfonate 14 (see Table 5). Even heating to
higher temperatures, increasing aldehyde loading or increasing
reaction time did not improve conversion of aldehyde and/or
yield of ketone 15j.
The generally higher yields observed on water may be
65 attributed to the higher concentration of reagents in the water-
based reaction conditions, perhaps due to a hydrophobic effect.
This may result in the radical intermediates under these
Conditions for reactions in 1,4-dioxane: n-butanal 5a (5 mmol) and vinyl
sulfonate 14 (1 mmol) were stirred at 300 rpm in 1,4-dioxane at 21°C for
the time specified. Conditions for reactions on H2O: n-butanal 5a (5
mmol) and vinyl sulfonate 14 (1 mmol) were stirred at 300 rpm in H2O at
10 21°C for the time specified. a Determined by integration of 1H NMR
relative to pentachlorobenzene as an internal standard.
With our optimised conditions in hand we sought to evaluate
the generality of our aerobically initiated hydroacylation protocol
with respect to aldehyde auto-oxidation rate. Thus, aldehydes
15 5a-j were specifically chosen to test this particular parameter as
they exhibited a broad range of oxidation rates (see Table 1) and
did not bear any complicating structural functionality. These
aldehydes were also selected in view of their wide range of
hydration equilibrium constants29,30 and their broad range of
20 solubilities in water,31 in order to evaluate whether these
parameters had any impact on yield of ketone in the water-based
reaction conditions (Table 5).
Table 5 Hydroacylation of vinyl sulfonate 14 with aldehydes 5a-j
5:17 in
Solubility
Yield 15 Yield 15 (1,4-
Aldehyde 5
5a
D2Oa
of 5/mass%c (H2O)/%d dioxane)/%d
1:1.04
1:0.86
5.48
4.57
78
65
40 (60)
58 (95)
5b
5c
5d
1:0.66
1:0.98
1.78
0.44
74
75
58
68
4
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conditions having
a
shorter lifetime, resulting in less
unfavourable unimolecular degradation pathways ensuing. This
hypothesis may also be supported by the noticeably lower yields
of ketone observed when using α-substituted aldehydes 5e and 5f
and α,α-disubstituted aldehyde 5i in the 1,4-dioxane conditions.
Presumably, their corresponding acyl radicals, in the 1,4-dioxane
5
conditions, have
unfavourable decarbonylation. This is particularly evident for the
hydroacylation of pivaldehyde 5i where 58% of decarbonylation 45 Scheme 4 An alternative route to gain access to enones from aldehydes
a
longer lifetime and undergo more
10 addition product was observed and only 5% of hydroacylation
product was isolated. Further support for this hypothesis is the
noticeably lower yield observed in 1,4-dioxane for the
hydroacylation of 14 with isovaleraldehyde 5c. The low yield of
ketone 15c was due to the formation of species 18, which is
15 almost certainly derived from acyl radical addition to 14,
followed by intramolecular hydrogen atom abstraction, addition
to another molecule of vinyl sulfonate 14 and intermolecular H-
atom abstraction. Although we were unable to isolate ketone 18,
we were able to carry out an elimination-addition sequence to
20 afford ketone 19, and therefore indirectly confirm its structure
(Scheme 3).
Keto-sulfonate 15a was chosen as our model γ-keto-PFP-
sulfonate to explore elimination to an enone. Encouragingly,
elimination was achieved under basic conditions via the
application of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU,
2
50 equivalents). Quantitative conversion of keto-sulfonate 15a to
enone 20a was readily confirmed by 1H NMR, relative to
pentachlorobenzene as an internal standard.37 However isolation
was not effected due to the rapid polymerisation of terminal
enones upon concentration after purification. Ketone 15a was
55 also subjected to a range of acidic conditions (acetic acid, para-
toluenesulfonic acid and pyridinium para-toluenesulfonate) in
various solvents (i.e. CH2Cl2, CHCl3, MeOH, Et2O, PhMe and
THF), but was found to be highly stable with complete recovery
of 15a being observed in all cases.
60
Scheme 5 Elimination of sulfonate from 15a to form enone 20a.
b. Elimination-Addition as an indirect alternative to the
hydroacylation of electron-rich alkenes
We envisaged that the conjugate addition of nucleophiles to
65 the enones generated by elimination of sulfonate from keto-
sulfonates may provide an indirect, reliable alternative to the
hydroacylation of electron rich alkenes (Scheme 6). Current
strategies toward the hydroacylation of electron rich alkenes
require the use of a polarity reversal catalyst and are often low to
70 moderate yielding.8,16,38,39 Moreover, as elimination is essentially
quantitative and there is a plethora of literature on the conjugate
addition of various nucleophiles to enones,40 we believe we can
access motifs such as 21 rapidly and in high yields.
Scheme 3 Formation of by-product 18 in the 1,4-dioxane conditions and
elimination-addition on ketone 18 to afford species 19
25 Synthetic utility of γ-keto-PFP-sulfonates
The disposition of the functional groups in a γ-keto-PFP-
sulfonate motif strongly suggests that this bi-functional motif has
appreciable potential for further manipulation. The carbonyl
group is a versatile moiety that can be used in various synthetic
30 transformations and, through the work pioneered by our group,
PFP-sulfonates have been shown to be useful alternatives to
sulfonyl chlorides for the synthesis of sulfonamides.32-35
a. Elimination of PFP-sulfonate to form enones
From the outset, the elimination of sulfonate from ketone 15 to
35 form enone 20 was seen as a highly desirable transformation as,
in conjunction with the hydroacylation chemistry, it represents a
mild overall method of converting an aldehyde to an enone
(Scheme 4). This is particularly relevant as, at present, aldehydes
are commonly converted to enones via the addition of a vinylic
40 metal species to form an allylic alcohol, which is then oxidised
(Scheme 4),36 i.e. relatively harsh reaction conditions. Thus, a
mild alternative to achieve the same overall transformation is
highly attractive.
75 Scheme 6 An indirect alternative to the hydroacylation of electron-rich
alkenes
Through our strategy, it should also be possible to access a
variety of unsymmetrical ketones, which would otherwise
represent a significant challenge to current methods for the
80 hydroacylation of electron rich alkenes, due to insurmountable
polarity mis-match. A case in point is the direct hydroacylation of
vinyl sulfides, a transformation that has, to the best of our
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Table 7 Conversion of ketone 15a to sulfonamides 23-25a
knowledge, no literature precedent despite the emergence of thiol
polarity reversal catalysis.38 Encouragingly, however, the indirect
hydroacylation-elimination-addition strategy described above
does provide access to these molecules, and in excellent yields
(Table 6).
5
Sulfonamide
Isolated yield/%
82
Table 6 Conversion of ketone 15a to γ-keto-sulfides 22
23a
γ-Keto-sulfide 22
Isolated yield/%
98
32
40
24a
25a
22a
97
35 Conditions: ketone 15a, amine (2 eq.), NMP, 0 °C to 21 °C.
22b
We also proceeded to show that secondary sulfonamide 23a
could be converted into sultam 26, in a one-pot reductive-
cyclisation protocol, in excellent yield (Scheme 7). It is envisaged
that a wide range of similar sultams may be synthesised in an
40 analogous manner.
Conditions: ketone 15a, DBU (2 eq.), thiol (1.3 eq.), CH2Cl2, 21 °C.
c. Formation of γ-keto-sulfonamides, sultams and sultones
from γ-keto-PFP-sulfonates
10
We next explored the possibility of converting γ-keto-
sulfonates into γ-keto-sulfonamides. To do this, initially we
applied our previously reported conditions for sulfonamide
synthesis from PFP-sulfonates (DBU, amine in THF)33 to the
conversion of PFP-sulfonate 15a into its n-hexylamine
15 sulfonamide analogue 23a. However, perhaps unsurprisingly,
keto-sulfonate 15a underwent almost exclusive elimination to its
corresponding enone under these reaction conditions. Application
of a weaker base, triethylamine, also appeared to promote enone
formation and generated minimal sulfonamide 23a (ca. 10%)
Scheme 7 Reductive cyclisation of 23a to afford sultam 26
We next turned our attention to the synthesis of cyclic
N-sulfonyl imines of the form of 27. Previously, they have been
45 accessed via a three step protocol reported by Freitag in 63-68%
overall yield.41 However, we were able to achieve direct access to
N-sulfonylimine 27 via the bubbling of ammonia gas into a
solution of γ-keto-sulfonate 15a in CH2Cl2 in 67% yield
(Scheme 8). Unlike the protocol outlined by Freitag, this method
50 represents a simple and mild route to cyclic N-sulfonylimines in
which analogue synthesis should be facile. Furthermore, through
the work pioneered by Zhou, access to 3-substituted chiral
sultams of the form of sultam 28 should be facile.42 The
molecules generated by Zhou’s asymmetric hydrogenation
55 protocol are important organic synthetic intermediates and
structural units of agricultural and pharmaceutical agents.43
20
In an attempt to facilitate further formation of sulfonamide 23a
the use of more polar solvents was explored. Encouragingly,
application of NMP as solvent gave desired sulfonamide 23a in
45% yield, with the major side-product being enone derived.
Lowering the temperature at which the amine was added, 0 °C,
25 suppressed elimination and resulted in an improved yield of 64%.
To further suppress elimination, an additional equivalent of the
nucleophilic amine was used in place of triethylamine, as it did
not promote elimination. To our delight, this resulted in a yield of
82%. The reaction protocol was then applied to a secondary
30 amine and a sterically encumbered primary amine, morpholine
and tert-butylamine, respectively (Table 7). Although this only
afforded modest yields of sulfonamides 24a and 25a, the protocol
provides reliable access to γ-keto-sulfonamides.
Scheme 8 Formation of cyclic N-sulfonylimine 27 from ketone 15a
Finally, we envisaged that access to sultones could be achieved
60 by reduction of the ketone moiety in keto-sulfonate 15a.
Gratifyingly, sodium borohydride reduction of the carbonyl group
in keto-sulfonate 15a gave access to sultone 29 in good yield
(Scheme 9).
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Organic & Biomolecular Chemistry
Scheme 9 Formation of sultone 29 from ketone 15a
Hydroacylation of vinyl phosphonates
We were particularly interested in the hydroacylation of vinyl
phosphonates as γ-ketophosphonates, and their corresponding
phosphonic acids, have been established as useful tools in both
synthetic chemistry44,45 and biology as non-hydrolysable
phosphate mimetics.46-49 Thus, we applied our optimised
protocols for the efficient hydroacylation of vinyl sulfonate 14 to
35
5
Scheme 11 Proposed mechanism for the formation of aldehyde 32
Despite the low yield observed for the hydroacylation of vinyl
phosphonate 30 with n-butanal 5a at 21 °C in 1,4-dioxane
(Scheme 10) we were sufficiently intrigued to embark upon an
10 the hydroacylation of vinyl phosphonate 30 (Scheme 10). As in
the case for the optimisation of the hydroacylation of vinyl
sulfonate 14, n-butanal 5a was chosen as the aldehyde component
in the initial reactions.
40 optimisation study. As n-butanal had been completely converted
to its corresponding acid under the reaction conditions and the
conversion of alkene was very low, we envisaged that controlling
exposure of the reaction mixture to molecular oxygen was key to
achieving efficient hydroacylation. Moreover, this would also
45 allow us, to some extent, suppress the formation of aldehyde 32.
We rationalised that control of the dissolved molecular oxygen
concentration and exposure of the reaction mixture to air could be
readily achieved by varying reaction temperature and the surface
area to volume ratio (Table 8).
50 Table 8 Hydroacylation of vinyl phosphonate 30 with aldehyde 5a at
various temperatures and concentrations
15
Scheme 10 Attempted hydroacylation of vinyl phosphonate 30 with
n-butanal 5a in 1,4-dioxane and water
Although no ketone was observed using the water-based
conditions, γ-ketophosphonate 31a was isolated using 1,4-
dioxane as solvent, albeit in very low yield (Scheme 10). In both
Surface area
/cm2:volume/
cm3 b
Isolated
31a:32:33c yield
31a/%
[30]a
Conversion
20 cases, complete conversion of aldehyde 5a was observed. The
lack of ketone observed in water was thought to be due to the
water solubility of vinyl phosphonate 30. The low yield in 1,4-
dioxane was attributed to inefficient trapping of the acyl radicals
generated under the reaction conditions by alkene 30, as
25 evidenced by the complete conversion of aldehyde and very low
Entry
T/C
20
/mol dm-3
30/%c
1
2
3
4
5
6
7
8
9
1.00
0.25
1.00
0.25
5.00
2.00
1.00
0.50
0.25
1.00
0.25
1:0.32
1:1.29
1:0.32
1:1.29
1:0.06
1:0.16
1:0.32
1:0.64
15
15
60
-
-
-
-
<5
<5
35
25
40
65
60
100
100
100
100
100
100
100
1:0.27:0.07 61
1:0.19:0.08 67
1:0.18:0.09 70
1:0.16:0.10 60
1:0.10:0.14 55
1
conversion of alkene, 15%. Careful examination of the crude H
NMR spectrum of the reaction in the 1,4-dioxane also indicated
the formation of aldehyde 32 and phosphonate 33. Phosphonate
33 is presumably formed via 1,4-dioxane radical addition to vinyl
30 phosphonate 30. Whereas aldehyde 32 is most likely the result of
peracyl radical 7a addition to vinyl phosphonate 30, to form 34,
followed by aldehydic hydrogen atom abstraction to form
peroxide 35, which then decomposes to aldehyde 32 and an
equivalent of butanoic acid 10a (Scheme 11).
1:1.29
1:0.32
1:1.29
10
11
80
-
-
69
57
Conditions: vinyl phosphonate 30 (1 mmol), n-butanal 5a (5 mmol),
1,4-dioxane (see table), temperature (see table), 24 h. a Concentration of
30 refers to initial concentration of 30 in 1,4-dioxane before addition of
55 5a. b Surface area refers to surface area exposed to air. c Determined by
integration of 1H NMR relative to pentachlorobenzene as an internal
standard.
Gratifyingly, increasing the reaction temperature had
a
dramatic impact on yield of γ-ketophosphonate 31a with optimal
60 yield afforded at 60 °C, 70%, at 1.00 mol dm-3 (Table 8, Entry 7);
heating to higher temperatures did not affect yield significantly
(Table 8, Entries 10 and 11). The increase in yield with
increasing temperature was attributed to the lower concentration
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Page 8 of 16
of dissolved molecular oxygen. This promotes acyl radical
trapping by vinyl phosphonate 30 rather than with molecular
low yields observed for aldehydes 5b and 5h, and the absence of
ketone formed on application of aldehydes 5i and 5j. The low
oxygen, resulting in higher conversion of alkene and a higher 30 yields observed for aldehydes 5b and 5h may be rationalised by
yield of γ-ketophosphonate 31a. The lower yields observed at
60 °C at concentrations above and below 1.00 mol dm-3 may be
rationalised by increased formation of aldehyde 32 and
phosphonate 33, respectively. The higher surface area to volume
the propensity of these aldehydes to undergo rapid auto-
oxidation, thus resulting in inefficient acyl radical trapping by
alkene 30. This hypothesis is supported by the complete
conversion of aldehyde and low conversion of alkene observed in
5
ratio at higher concentrations results in an increased exposure to 35 both cases. The absence of the formation of γ-ketophosphonate
air and hence promotes the likelihood of an acyl radical being
31i for the hydroacylation of vinyl phosphonate 30 with
pivaldehyde 5i was due to the significant amount of tert-butyl
radical addition that took place under the reaction conditions,
10 trapped by molecular oxygen rather than by an alkene, thus
lowering the yield of γ-ketophosphonate 31a and decreasing the
31a:32 ratio (Table 8, Entries 5-7). Unsurprisingly, at lower
resulting
in
the
formation
of
dimethyl
(3,3-
concentrations, a decreased 31a:33 ratio was observed due to the 40 dimethylbutyl)phosphonate in 46% yield (see Table 9 and ESI).
greater relative concentration of 1,4-dioxane to vinyl phosphonate
15 30, consequently, lowering the yield of γ-ketophosphonate 31a
and increasing the yield of yield of 33 (Table 8, Entries 7-9).
With optimised conditions in-hand, we then examined the
The tert-butyl radical is presumably derived from
decarbonylation of the acyl radical formed from pivaldehyde
oxidation. Consistent with our previous study on the
hydroacylation of vinyl sulfonate 14 (see Table 5), aldehyde 5j
scope of hydroacylation of vinyl phosphonate 30. The same set 45 gave 0% conversion of alkene since no aldehyde was oxidised.
of functionally simple aldehydes that exhibit a broad range of
20 auto-oxidation rates, 5a-j, employed in the analysis of vinyl
Hydroacylation of α,β-unsaturated esters
We next applied our methodology to the hydroacylation of α,β-
unsaturated esters to generate 1,4-dicarbonyls, which are
extremely useful intermediates. To investigate this, we initially
50 applied our optimised protocols for the efficient hydroacylation
of vinyl sulfonate 14 to the hydroacylation of 1,2-diester alkene
35 (Scheme 12), which has classically shown promise as an acyl
radical acceptor.8 As in the case for the hydroacylation of vinyl
sulfonate 14 and vinyl phosphonate 30, n-butanal was selected as
55 the aldehyde component in these reactions.
sulfonate 14 (see Table 5) were applied to reaction with 30.
Table 9 Hydroacylation of vinyl phosphonate 30 with aldehydes 5a-j
Isolated Yield
Aldehyde 5
5a
Conversion 30/%
31/%a
100
70
65
40
5b
5c
100
100
65
72
5d
5e
100
100
60
52
Scheme 12 Attempted hydroacylation of alkene 35 with n-butanal 5a in
1,4-dioxane and water. * Determined by integration of 1H NMR relative
to pentachlorobenzene as an internal standard by analogy with similar
60
products
5f
5g
100
38
55
21
We were pleased to isolate ketone 36a in the 1,4-dioxane
conditions, albeit in low yield. However, no ketone was isolated
from the water-based conditions. The lack of ketone under the
water conditions was thought to be due to inefficient trapping of
5h
60
0
0b
65 the acyl radical with alkene 35 as complete conversion of
aldehyde and low conversion of alkene was observed under the
reaction conditions. This may be a consequence of the exposure
to molecular oxygen in the water conditions being much higher
than in 1,4-dioxane, and too high to be compatible with alkene
70 35. Also isolated from the crude reaction mixture in the 1,4-
dioxane conditions was cyclic peroxide 37, which is presumably
derived from addition of molecular oxygen to the adduct radical
formed by addition of acyl radical 6a to alkene 38, to form 39,
which then undergoes cyclisation and H-atom abstraction to form
75 the cyclic peroxide (Scheme 13).
5i
0
5j
Conditions: vinyl phosphonate 30 (1 mmol), aldehyde 5 (5 mmol),
1,4-dioxane (1 mL), 60 °C, 24 h. a Isolated yield unless otherwise stated.
25 b Dimethyl (3,3-dimethylbutyl)phosphonate isolated in 46% yield.
In general, moderate to good yields were observed across the
aldehyde series. The major exceptions to this were the relatively
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decreased, higher conversion of alkene 35, decreased formation
of cyclic peroxide 37, and a higher yield of ketone 36a was
observed. Optimal yield for the hydroacylation of dimethyl
maleate 35 with n-butanal 5a was observed at 0.33 mol dm-3.
40 Table 11 Hydroacylation of alkene 35 with aldehyde 5a at various
concentrations
Scheme 13 Proposed mechanism for the formation of peroxide 37
As in the case for the hydroacylation of vinyl phosphonate 30,
in the 1,4-dioxane conditions, n-butanal had been completely
converted under the reaction conditions and the conversion of
alkene was very low. Thus, we again rationalised that controlling
the exposure of the reaction mixture to molecular oxygen by
manipulating reaction temperature and concentration would be
vital for efficient hydroacylation.
Increasing the temperature from 20 ºC to 60 ºC gave an
increase in the yield of ketone 36a, although heating to higher
temperatures led to decomposition of the ketone product (Table
10). The increase in yield observed at higher temperature was
thought to be a consequence of the lower concentration of
5
Surface area
/cm2:volume/cm3 b
1:0.06
Yield
36a/%c
37
35
50
64
77
74
70
[35]a/mol dm-3
Conversion/%c
36a:37c
5.00
2.00
1.00
0.50
0.33
0.25
0.20
50
60
85
100
100
100
100
1:0.34
1:0.22
1:0.07
1:0.05
1:0.04
1:0.03
1:0.03
1:0.16
1:0.32
1:0.64
1:0.96
1:1.29
1:1.61
10
15 dissolved molecular oxygen in solution. This would result in a
higher conversion of alkene 35 as an acyl radical would more
likely be trapped by an alkene than react with molecular oxygen;
thus resulting in a higher yield of 36a. Moreover, the lower
concentration of molecular oxygen also decreased the 36a:37
20 ratio from 1:0.38 to 1:0.15 in the 20-80 ºC range. This is likely to
be a consequence of adduct radical 38 in the reaction mechanism
(see Scheme 13) having a greater propensity to abstract an
aldehydic hydrogen atom than undergo addition to molecular
oxygen; thus suppressing formation of peroxide and encouraging
25 formation of ketone 36a.
Conditions: alkene 35 (1 mmol), n-butanal 5a (5 mmol), 1,4-dioxane (see
table), 60 °C, 8 days.. a Concentration of 35 refers to initial concentration
of 35 in 1,4-dioxane before addition of 5a. b Surface area refers to surface
45 area exposed to air. c Determined by integration of 1H NMR relative to
pentachlorobenzene as an internal standard.
A
similar trend in yields, to that obtained for the
hydroacylation of dimethyl maleate 35 with n-butanal 5a with
respect to changing surface area:volume, was observed for the
50 hydroacylation of diethyl maleate 40 and dimethyl fumarate 41
with n-butanal 5a (Table 12). The good yields observed for the
hydroacylation of diethyl maleate 40 and dimethyl fumarate 41
also showed that the efficiency of the hydroacylation protocol is,
to some extent, independent of the nature of the ester and/or
55 alkene geometry (E/Z).
Table 10 Hydroacylation of alkene 35 with aldehyde 5a at various
temperatures
Table 12 Hydroacylation of alkenes 40 and 41 with aldehyde 5a at
various concentrations
[alkene]a/mol
dm-3
Surface area
/cm2:volume/cm3 b
1:0.16
Isolated yield
Isolated yield
Temperature/°C Conversion 35/%b Yield 36a/%b
36a:37b
1:0.38
1:0.25
1:0.19
1:0.15
42/%
47
68
55
36a/%
30
62
50
20
40
60
80
40
60
60
85
21
27
35
24
2.00
0.33
0.20
1:0.96
1:1.61
Conditions: alkene (1 mmol), n-butanal 5a (5 mmol), 1,4-dioxane (see
table), 60 °C, 8 days.. a Concentration of alkene refers to initial
60 concentration of alkene in 1,4-dioxane before addition of 5a. b Surface
area refers to surface area exposed to air.
Conditions: alkene 35 (1 mmol), n-butanal 5a (5 mmol), 1,4-dioxane
(0.5 mL), temperature, 8 days.. a Determined by integration of 1H NMR
30 relative to pentachlorobenzene as an internal standard.
It was also reasoned that the surface area to volume ratio may
have a significant impact on the exposure of the reaction medium
to air, and thus, the effect of changing surface area:volume was
explored (Table 11). For reasons analogous to those discussed for
35 vinyl phosphonate 30, as the surface area to volume ratio
With a view to increase the scope of 1,4-dicarbonyls that can
be formed by our methodology, we applied our optimised
conditions to the hydroacylation of 1,1-diester alkene 43 and 2-
65 alkoxy-1,1-diester alkene 45. Gratifyingly, very good yields of
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ketones 44a and 46a, respectively, were obtained (Scheme 14).
We were particularly encouraged by the excellent yield of ketone
46a since it demonstrates the mild nature of our protocol as one
In all cases, and perhaps as expected, aldehydes that rapidly
auto-oxidise to acid (i.e. aldehydes 5b, 5h and 5i, see Table 1)
gave low or no yield of ketone due to inefficient trapping of their
might imagine that this species is prone to elimination under ionic 20 corresponding acyl radicals by alkenes compared to the rate of
5
conditions. Thus, our protocol gives us access to products that
would otherwise be challenging to synthesise via alternative
ionic-based methods.
direct auto-oxidation. Moreover, in concert with our previous
studies, aldehyde 5j, yielded no ketone and underwent no
observable conversion to acid.
As expected, owing to the more electrophilic nature of 1,1-
25 diester alkene 43 compared with 1,2-diester alkene 35 and the
inherently more electrophilic adduct radical formed upon acyl
radical addition, higher yields were generally observed for the
hydroacylation of alkene 43 over alkene 35. It was also notable
that reaction with 1,2-diester alkene 35 over 1,1-diester alkene 43
30 appeared to be more sensitive to steric hindrance, as evidenced by
the yields observed for reaction with a variety of α-substituted
aldehydes (Table 13, Entries 2, 5 and 6).
Interestingly, we were able to isolate various sensitive ketones,
formed by the hydroacylation of alkene 45 with linear aldehydes
35 5a, 5c, 5d and 5g in excellent yields (Table 13, Entries 1, 3, 4 and
7). However, reaction with α-substituted aldehydes afforded no or
very low yields (Table 13, Entries 2, 5 and 6). These results
perhaps further highlight the sensitivity of acyl radical addition to
highly substituted alkenes. Nevertheless, an array of valuable
40 ketones were synthesised using our protocol.
Scheme 14 Hydroacylation of alkenes 43 and 45 with aldehyde 5a
10
Having established optimised conditions for the
hydroacylation of a range of α,β-unsaturated esters with n-butanal
5a, we next explored aldehydes with a range of auto-oxidation
rates, 5a-j (Table 13).
Table 13 Hydroacylation of alkenes 35, 43 and 45 with aldehydes 5a-j
Hydroacylation of azodicarboxylates
Eager to extend our methodology to C-N bond formation, we
applied our optimised conditions for the hydroacylation of vinyl
sulfonate 14 to the hydroacylation of azodicarboxylate 47
45 employing n-butanal as the aldehyde component.
Using either 1,4-dioxane or water as solvent, excellent yields
of acyl hydrazide 48a were observed (Table 14, Entries 1 and 7).
Given the high yields achieved and the lack of appreciable side-
products, except butanoic acid, we took the opportunity to assess
50 whether aldehyde stoichiometry could be reduced whilst
maintaining high yield (Table 14).
Entry
1
Aldehyde 5
5a
Ketone 36 Ketone 44 Ketone 46
70
76
87
2
21
42
0
5b
5c
Table 14 Hydroacylation of DIAD 47 with aldehyde 5a in 1,4-dioxane
and water
3
4
57
76
60
72
85
87
5d
5e
5
6
56
25
74
52
24
0
Isolated yield
Entry
Solvent
5a/eq.
47/eq.
48a/%
94
80
72
64
65
67
92
1
2
3
4
5
1,4-Dioxane
5
2
1.5
1
1
1
1
1
1
1
1.2
2
5f
5g
7
8
60
0
72
0
89
0
6
7
5h
H2O
2
1
8
9
10
11
1.5
1
1
1
1
1.2
2
90
70
90
91
9
0
0
0
0
0
0
5i
1
10
Conditions for 1,4-dioxane: DIAD 47, n-butanal 5a, 1,4-dioxane, 21 °C,
55 24 h. Conditions for H2O: DIAD 47 and n-butanal 5a, H2O, 21 °C, 24 h.
5j
Using 1,4-dioxane as solvent we saw a significant decrease in
yield on reducing the quantity of aldehyde (Table 14, Entries 1-
15 Conditions: alkene (1 mmol), aldehyde 5 (5 mmol), 1,4-dioxane (3 mL),
60 °C.
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3). In contrast, reducing the 5a:47 ratio from 2:1 to 1.5:1 in the
water-based conditions resulted in similarly high yields (Table
hydroacylation, even when using a single equivalent of aldehyde.
As in the case for the hydroacylation of vinyl sulfonate 14, under
14, Entries 7 and 8). However, only modest conversion (70%) 30 the water-based conditions, the use of acetaldehyde 5h gave no
was achieved with stoichiometric reaction conditions (Table 14,
Entry 9). The lower yield observed on reaction with a 1:1
stoichiometry of 5a:47 was attributed to conversion of
conversion of the double bond acceptor species due to its high
solubility in, and reactivity with, water. Perhaps most
interestingly, aldehyde 5j, which did not appear to auto-oxidise
(see Table 1) and did not undergo any conversion with any of the
5
diisopropyl
azodicarboxylate
47
to
diisopropyl
hydrazinedicarboxylate. To counter this, the amount of 35 other acceptors (see Tables 5, 9 and 13), afforded a good yield of
diisopropyl azodicarboxylate 47 was increased (Table 14, Entries
acyl hydrazide 48j (71%). These results seem to indicate that
azodicarboxylates are exceptionally good acyl radical acceptors
and/or that the adduct radicals generated from acyl radical
addition to azodicarboxylates are exceptionally efficient aldehyde
40 H-atom abstractors.
10 10 and 11), and gratifyingly, this afforded hydrazide 48a in
excellent yield, 90%, based on n-butanal as the limiting reagent.
A similar approach was applied to using 1,4-dioxane as solvent,
however, this brought limited success (Table 14, Entries 4-6).
With our optimised conditions in hand, we sought to evaluate
15 the tolerance of azodicarboxylate 47 to aldehydes with a range of
auto-oxidation rates. To appraise this, aldehydes 5a-j (1
equivalent) were reacted with azodicarboxylate 47 (1.2
equivalents) in H2O (Table 15).
Synthetic utility of acyl hydrazides
We then sought to explore the synthetic utility of acyl
hydrazides as acyl donors owing to the stabilised leaving group
that would be released upon an addition-elimination reaction at
45 the amide moiety. To do this, reaction of hydrazide 48a with
various amines was explored. Reaction with primary amines
afforded the corresponding amides 49a-c in excellent yields with
concurrent isolation of diisopropyl hydrazinedicarboxylate 50
(Table 16). Unfortunately, however, treatment of hydrazide 48a
50 with bulkier amines such as morpholine and pyrrolidine resulted
in low or no yield of amide 49. Use of more polar solvents, such
as DMF and NMP, did not improve yield and/or conversion.
Table 15 Hydroacylation of DIAD 47 with aldehydes 5a-j
Aldehyde 5
5a
Isolated yield 48/%
91
Table 16 Conversion of hydrazide 48a to amide 49 with concurrent
isolation of diisopropyl hydrazinedicarboxylate 50
79
5b
5c
79
88
5d
5e
Amide 49
Isolated yield/%
96
84
86
49a
49b
49c
95
98
5f
5g
85
0
5h
69
71
5i
19
25
49d
5j
20 Conditions: DIAD 47 (1.2 mmol), aldehyde 5 (1 mmol), H2O (1 mL),
21 °C for the time specified in the ESI.
49e
55 Conditions: acyl hydrazide 48a and amine (2.5 eq.), CH2Cl2, 21 °C.
Hydroacylation of azodicarboxylate 47 showed excellent
tolerance of aldehydes with a broad range of auto-oxidation rates.
Previously, our protocol has shown relatively poor tolerance for
25 aldehydes that auto-oxidise rapidly, i.e. aldehydes 5b and 5i.
However, when employing azodicarboxylate 47 as the acyl
radical acceptor component, these aldehydes underwent efficient
Upon close examination of the crude reaction mixtures for the
reaction of acyl hydrazide 48a with secondary amines we were
able to identify that the low yields of amides 49d-e was due to
attack of the amine at the carbamate ester, resulting in the
60 formation of 51.
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10 Table 17 Conversion of hydrazide 52 to amide 49
Scheme 15 Formation of 51 derived from attack of amine on the
carbamate of 48a
Amide 49
Isolated yield/%
59
In an attempt to obviate this unfavourable side-reaction, Boc
functionalised acyl hydrazide 52 was synthesised and submitted
to the aminolysis reaction conditions with secondary amines
morpholine and pyrrolidine. Gratifyingly, this significantly
improved yield of tertiary amides 49d and 49e as it presumably
suppressed attack at the carbamate (Table 17).
5
49d
49e
75
Conditions: acyl hydrazide 52 and amine (2.5 eq.), CH2Cl2, 21 °C.
Application of functionalised aldehydes
Having evaluated the tolerance of our hydroacylation protocol
to aldehydes with a range of auto-oxidation rates in concert with
15 various double bond acceptor moieties, we proceeded to appraise
functional group tolerance. Thus, the hydroacylation of vinyl
sulfonate 14, vinyl phosphonate 30, α,β-unsaturated ester 43 and
azodicarboxylate 47, under the optimised conditions that have
been developed for each acceptor, with aldehydes 5k-5w were
20 evaluated.
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DynamiDcOAI: 1r0t.i1c0l3Ve9ie/wLC3AiOnrtBikc4les1O6n►3l2inAe
Organic & Biomolecular Chemistry
Page 13 oJf 1o6urnal Name
Cite this: DOI: 10.1039/c0xx00000x
www.rsc.org/xxxxxx
ARTICLE TYPE
Table 18 Hydroacylation of vinyl sulfonate 14, vinyl phosphonate 30, α,β-unsaturated ester 43 and azodicarboxylate 47 with aldehydes 5k-5w
Entry
1
Aldehyde 5
Vinyl sulfonate 14a
Vinyl phosphonate 30a
1,1-Diester alkene 43a
DIAD 47a
64
57
62
87
5k
2
68
67
71
80
5l
3
4
62
81
71
74
67
68
70
82
5m
5n
5o
5
6
7
0
62
20b
0
60
0
74
42
54
0 (37)
0 (32)
5p
0
5q
5r
8
9
66
68
61
87
75
0 (0)
0 (0)
0 (0)
5s
10
11
0 (0)
0 (0)
0 (0)
55
75
5t
10 (35)
27 (55)
<5b (10)
5u
12
13
8b (32)
<5b (40)
<5b (35)
<5b (10)
<5b (10)
79
44
5v
<5b (10)
5w
Conditions for the hydroacylation of vinyl sulfonate 14: alkene 14 (1 mmol), aldehyde 5 (2 mmol), H2O (1 mL), 21 °C for the time specified in the ESI.
Conditions for the hydroacylation of vinyl phosphonate 30: alkene 30 (1 mmol), aldehyde 5 (5 mmol), 1,4-dioxane (1 mL), 60 °C, 24 h. Conditions for the
hydroacylation of 1,1-diester alkene 43: alkene 43 (1 mmol), aldehyde 5 (5 mmol), 1,4-dioxane (1 mL), 60 °C for the time specified in the ESI. Conditions
5 for the hydroacylation of DIAD 47: DIAD 47 (1.2 mmol), aldehyde 5 (1 mmol), H2O (1 mL), 21 °C for the time specified in the ESI. a All reactions
proceeded with 100% conversion of acceptor unless otherwise stated in parenthesis. b Determined by integration of 1H NMR relative to
pentachlorobenzene as an internal standard by analogy with similar products.
To our delight, excellent tolerance of cyclopropyl, ester, acetal
and alcohol functional groups was observed across all four
10 double bond acceptors (Table 18, Entries 1-4). Although epoxide-
bearing aldehyde 5o showed excellent tolerance of acceptors 30,
Consistent with a radical mechanism was the poor tolerance of
our methodology to aldehydes bearing alkenes (Table 18, Entries
6 and 7), presumably due to polymerisation under the reaction
conditions. The only exception to this was the moderate yields
43 and 47, no ketone was isolated on reaction with vinyl 20 observed when using azodicarboxylate as acceptor; further
sulfonate 14 (Table 18, Entry 5). In this case, although alkene
testament to azodicarboxylates being excellent radical acceptors
and/or their acyl radicals adducts being excellent chain
propagators. To probe whether it was specifically the alkene
was completely consumed under the reaction conditions, only a
1
15 polymeric substance could be observed in the crude H NMR.
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View ArtiPcleaOgnleine14 of 16
DOI: 10.1039/C3OB41632A
functionality that limited yield of hydroacylation product, the
corresponding reduced aldehyde of citronellal, 5r, was employed
under each of the reaction conditions (Table 18, Entry 8). As
most importantly, with exceptional retained enantiomeric
excesses (ree). Although no ketone could be isolated for reaction
of aldehyde 5y with vinyl sulfonate 14, acyl hydrazide 47y could
aldehyde 5r provided good to excellent yields of hydroacylation 50 be isolated in good yield, and again, with excellent retained
5
product in all cases, and as it has a similar auto-oxidation rate to
citronellal 5q, this supports the theory of poor tolerance of alkene
functional groups specifically. Consistent with our previous
results, aldehydes 5s and 5t, which did not appear to undergo
enantiomeric excess. These reactions represent to the best of our
knowledge the first examples of hydroacylation achieved with a
chiral aldehyde with retention of enantiomeric excess.
In concert with our auto-oxidation study, although all of
oxidation in our auto-oxidation study, only underwent reaction 55 aldehyde 5y was consumed on reaction with vinyl sulfonate 14,
10 with azodicarboxylate 47 (Table 18, Entries 9 and 10).
none of the corresponding acid was observed. The only species
observed in the crude 1H NMR were acetaldehyde 5h and
unreacted vinyl sulfonate 14. One possible explanation for the
formation of acetaldehyde 5h is via decarbonylation of the
The tolerance of aromatic aldehydes under our optimised
conditions was evaluated with electron-poor, -neutral and -rich
aldehydes 5u-w (Table 18, Entries 11-13). In general, our
hydroacylation protocol showed poor tolerance to aromatic 60 corresponding acyl radical of aldehyde 5y, followed by β-TBS-
15 aldehydes, with the only exception being observed for the
hydroacylation of azodicarboxylate 47; further evidence of the
exceptional propensity of azodicarboxylates to undergo efficient
hydroacylation. The major obstacle to efficient hydroacylation
elimination. In the presence of azodicarboxylate, however, such a
pathway may have been precluded, to some extent, by the rapid
reaction of acyl radicals with azodicarboxylates.
Having developed an effective protocol for the hydroacylation
with the alkene based double bond acceptors was centred on low 65 of acceptors using aldehydes bearing α-enantioenriched
20 conversion of alkene, unfavourable polymerisation and 1,4-
dioxane addition products. These side-reactions are likely to be a
consequence of inefficient aromatic acyl radical trapping by
alkenes, perhaps due to unfavourable steric interactions and/or
stereocentres in excellent ree, we proceeded to explore whether
acyl hydrazide 47x may be converted into an amide with high ree.
To our delight, reaction with benzylamine afforded known amide
53 in good yield, and most significantly, with retention of
inefficient aldehyde H-atom abstraction by the resultant acyl 70 stereochemical information. We envisage that
25 radical-alkene adduct radical species.
a
range of
enantioenriched amides may be prepared in similarly high
enantiomeric excess.
Application of enantiopure aldehydes
Due to acyl radicals being σ-type radicals we envisaged that
aldehydes bearing α-stereocentres would undergo hydroacylation
with preservation of enantiopurity. Thus we evaluated the use of
30 chiral non-racemic aldehydes 5x and 5y in our hydroacylation
protocol. As valuable enantiopure aldehydes would almost
certainly not be employed when a vast excess of aldehyde is
Scheme 16 Conversion of hydrazide 47a to amide 53
required (e.g.
5 equivalents), hydroacylation with chiral
75 Conclusions
aldehydes 5x and 5y was only analysed on reaction with vinyl
35 sulfonate 14 and azodicaroboxylate 47 where only 2 and 1
equivalent(s) is/are employed, respectively.
In conclusion, we have described the use of aerobic aldehyde
C-H activation for the construction of C-C and C-N bonds
through the hydroacylation of vinyl sulfonates and phosphonates,
α,β-unsaturated esters and azodicarboxylates. These reactions
80 require no metal(s) and rely on only molecular oxygen in air for
Table 19 Hydroacylation of vinyl sulfonate 14 and DIAD 47 with
aldehydes 5x-y
activation, therefore providing
a clean, green route to
hydroacylation. Of particular note is the hydroacylation of
azodicarboxylates, which proceeded with aldehyde as limiting
reagent, a stoichiometry not previously observed in the literature.
85 Hydroacylation, in all acceptor cases, was shown to proceed in
good yields for a range of aldehydes with respect to oxidation
rate, as well as being tolerant of aldehydes bearing various
functional groups. Moreover, the use of chiral aldehydes for
hydroacylation, which has not been previously reported, was
90 shown to be applicable to our aerobic activation protocol with
exceptional retention of enantiomeric excesses observed in all
cases. Throughout, we have observed products and patterns of
reactivity that are most readily explained though a radical
mechanism. In addition to using aerobic aldehyde C-H activation
95 to affect hydroacylation of a range of acyl radical acceptors, the
reactivity of the resultant hydroacylation products has also been
demonstrated. The γ-keto-sulfonate motif may act as a precursor
Aldehyde 5
Vinyl sulfonate 14a
DIAD 47a
77, 97%ee
88, 98%ee
5x
0 (25)
61, 99%ee
5y
Conditions for the hydroacylation of vinyl sulfonate 14: alkene 14 (1
40 mmol), aldehyde 5 (2 mmol), H2O (1 mL), 21 °C for the time specified in
the ESI. Conditions for the hydroacylation of DIAD 47: DIAD 47 (1.2
mmol), aldehyde 5 (1 mmol), H2O (1 mL), 21 °C for the time specified in
the ESI. a All reactions proceeded with 100% conversion of acceptor
unless otherwise stated in parenthesis.
45
To our delight, aldehyde 5x underwent efficient
hydroacylation with both vinyl sulfonate 14 and DIAD 47, and
for
the
formation
of
γ-keto-sulfonamides,
sultams,
N-sulfonylimines and sultones. Perhaps most significantly, the
14
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DOI: 10.1039/C3OB41632A
Page 15 of 16
Organic & Biomolecular Chemistry
γ-keto-sulfonate motif may undergo quantitative elimination to 55 1 h. The solvent was removed in vacuo and the crude residue
generate enones, providing a mild alternative route for the overall
conversion of an aldehyde to an enone when taken in conjunction
with the hydroacylation chemistry. Moreover, the hydroacylation-
elimination-addition chemistry represents a powerful indirect
alternative for the hydroacylation of electron rich alkenes, and the
acyl hydrazide motif has also been highlighted as an intermediate
for the construction of amides.
purified as described in the ESI to afford the desired γ-keto-
sulfide.
Typical procedure for the synthesis of sulfonamides 23-25a
5
To a solution of pentafluorophenyl 3-oxohexane-1-sulfonate 15a
60 (0.29 mmol) in NMP (2.5 mL) was added dropwise a solution of
amine (0.58 mmol) in NMP (1 mL) at 0 °C. After addition was
complete, the reaction mixture was warmed to 21 °C and stirred
for 4 h. To work-up, the reaction mixture was diluted with Et2O
(20 mL), washed with sat. LiCl (3 × 20 mL), sat. NaHCO3 (3 ×
65 20 mL), 2M HCl (3 × 20 mL), dried (MgSO4) and the solvent
removed in vacuo to afford the desired sulfonamide.
Experimental
10 General
All reagents were purchased from Aldrich or AlfaAesar and were
used as received without further purification. All hydroacylation
reactions were carried out in stoppered carousel tubes (15 cm × 2
cm) equipped with an octagon-shaped magnetic stirrer bar (12.7
15 mm × 3 mm). Where described below petrol refers to petroleum
ether (40-60 °C). All reactions were monitored by thin-layer
chromatography (TLC) on pre-coated silica gel plates (254 µm).
Flash column chromatography was carried out with Kiesegel
60M 0.04/0.063 mm (200-400 mesh) silica gel. 1H NMR spectra
20 were recorded at 300 MHz, 400 MHz, 500 MHz and 600 MHz
and 13C NMR at 75 MHz, 100 MHz, 125 MHz and 150 MHz on
a Bruker AMX300, AMX400, AMX500 and AMX600 at 21 °C
Typical procedure for hydroacylation of vinyl phosphonate
30
To a solution of vinyl phosphonate 30 (1 mmol) in 1,4-dioxane (1
70 mL) was added aldehyde (5 mmol) and the reaction mixture
stirred at 300 rpm at 60 °C for 24 h unless otherwise stated in the
ESI. The reaction mixture was concentrated in vacuo and the
crude residue purified as described in the ESI to afford the
desired γ-ketophosphonate.
75 Typical procedure for the hydroacylation of alkenes 35, 40,
41, 43 and 45
1
temperature. The chemical shifts () for H and 13C are quoted
To a solution of alkene (1 mmol) in 1,4-dioxane (3 mL) was
added aldehyde (5 mmol) and the reaction mixture stirred at 300
rpm at 60 °C for the time specified in the ESI. The solvent
80 removed in vacuo and the crude residue purified as described in
the ESI to afford the desired hydroacylation product.
relative to residual signals of the solvent on the ppm scale.
25 Coupling constants (J values) are reported in Hertz (Hz). Mass
spectra were obtained on a VG70-SE mass spectrometer. Infrared
spectra were obtained on a Perkin Elmer Spectrum 100 FTIR
Spectrometer operating in ATR mode. Optical rotations were
measured using a Perkin Elmer 343 polarimeter. Chiral High
30 Performance Liquid Chromatography (HPLC) was performed on
a Varian HPLC instrument equipped with a manual injector,
binary pump, and a UV detector (214 nm) using CHIRALCEL®
Typical procedure for the hydroacylation of DIAD 47
To a mixture of azodicarboxylate (1.2 mmol) and H2O (500 μL)
was added aldehyde (1.0 mmol) and the reaction mixture stirred
85 at 300 rpm at 21 °C for the time specified in the ESI. The solvent
was removed in vacuo and the crude residue purified as described
in the ESI to afford the desired hydroacylation product.
OD column (4.6 mm
x 250 mm, 10 μm) from Chiral
Technologies (West Chester, PA) eluting with hexane:i-PrOH.
35 Typical procedure for the hydroacylation of vinyl sulfonate
14 in 1,4-dioxane
Typical procedure for the synthesis of amides 49a-c from acyl
hydrazide 48a
To a solution of ethenesulfonic acid pentafluorophenyl ester 14 (1
mmol) in 1,4-dioxane (1 mL) was added aldehyde (5 mmol) and
the reaction mixture stirred at 300 rpm at 21 °C until reaction was
40 complete by TLC. PhMe (2 mL) was added and the solvent
removed in vacuo and the crude residue purified as described in
the ESI to afford the desired ketone sulfonate ester.
90 To
a
solution of dipropan-2-yl 1-butanoylhydrazine-1,2-
dicarboxylate 48a (1 mmol) in CH2Cl2 (2 mL) was added amine
(2.5 mmol) and the reaction mixture stirred at 300 rpm at 21 °C
for 16 h. The solvent was removed in vacuo and the crude residue
purified as described in the ESI to afford the desired amide.
95 Typical procedure for the synthesis of amides 49d-e from acyl
hydrazide 52
Typical procedure for the hydroacylation of vinyl sulfonate
14 in H2O
To
a
solution of di-tert-butyl 1-butanoylhydrazine-1,2-
45 To a solution of ethenesulfonic acid pentafluorophenyl ester 14 (1
mmol) in H2O (1 mL) was added aldehyde (2 mmol) and the
reaction mixture stirred at 300 rpm at 21 °C until reaction was
complete by TLC. The solvent removed in vacuo and the crude
residue purified as described in the ESI to afford the desired
50 ketone sulfonate ester.
dicarboxylate 52 (1 mmol) in CH2Cl2 (2 mL) was added amine
(2.5 mmol) and the reaction mixture stirred at 300 rpm at 21 °C
100 for 16 h. The solvent was removed in vacuo and the crude residue
purified as described in the ESI to afford the desired amide.
Acknowledgements
Typical procedure for the synthesis of γ-keto-sulfides 22
We gratefully acknowledge UCL for support of our programme.
We also thank A. G. Davies and K. U. Ingold for helpful
105 discussions.
To a solution of pentafluorophenyl 3-oxohexane-1-sulfonate 15a
(1 mmol) in CH2Cl2 (3 mL) was added thiol (1.3 mmol) and DBU
(2 mmol), and the reaction mixture stirred at 300 rpm at 21 °C for
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DOI: 10.1039/C3OB41632A
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Department of Chemistry, University College London, 20 Gordon Street,
London, WC1H OAJ, UK. Fax: +44 (0)20 7679 7463; Tel: +44 (0)20
3108 5071; E-mail: VPEnterprise@ucl.ac.uk
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