α-Aroyloxyaldehydes: Scope and limitations as alternatives to α-haloaldehydes for NHC-catalysed redox transformations

Article abstract of DOI:10.1039/c0cc02456b

α-Aroyloxyaldehydes are readily prepared bench stable synthetic intermediates. Their ability to act as α-haloaldehyde surrogates for NHC-promoted redox esterifications and in [4+2] cycloadditions is described.

Full text of DOI:10.1039/c0cc02456b

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a-Aroyloxyaldehydes: scope and limitations as alternatives to
a-haloaldehydes for NHC-catalysed redox transformationswz
Kenneth B. Ling and Andrew D. Smith*
Received 9th July 2010, Accepted 6th August 2010
DOI: 10.1039/c0cc02456b
a-Aroyloxyaldehydes are readily prepared bench stable synthetic
intermediates. Their ability to act as a-haloaldehyde surrogates
for NHC-promoted redox esterifications and in [4+2] cyclo-
additions is described.
Model studies considered the internal redox reactions
of a-benzyloxy and a-phenoxyaldehydes 1 and 4. While a-benzyl-
oxyaldehyde 1 proved inert to NHC-mediated catalysis, under
identical conditions facile and quantitative rearrangement of
a-phenoxyaldehyde 4 to phenyl ester 5 was observed (Scheme 1).
Scheidt and co-workers have described similar observations,13
consistent with the leaving group ability of the a-functional group
being important in these transformations. Although these results
were instructive, the lack of a general synthetic route to prepare
bespoke a-substituted a-phenoxyaldehydes meant that alternative
a-functionalised aldehydes were considered.
N-Heterocyclic carbenes (NHCs) have been used to promote a
diverse range of organocatalytic transformations in recent
years.1 Among these advances, the ability of NHCs to mediate
oxidative esterification and amidation reactions of aldehydes
has been demonstrated.2 Strategies in this area typically use
either an NHC in combination with an oxidant,3 or proceed
through a redox process using an a-functionalised aldehyde.4
Representative substrates for such redox processes include
enals,5 a-haloaldehydes6 and epoxyaldehydes,7 which all
undergo facile NHC-promoted esterifications, but require an
additive such as HOBt, imidazole or 1,2,4-triazole to achieve
amidations.8 Bode and co-workers have recently promoted
a0-hydroxyenones as attractive surrogates for enals in a variety
of NHC-promoted reactions9 including amidations,10 due to
their simple preparation, crystallinity and long-term stability.
Given our interest in NHC-mediated reactions,11 coupled with
the potential synthetic versatility of these a-functionalised
aldehyde substrates, we took inspiration from this work, and
aimed to develop alternative bench stable substrates to
a-haloaldehydes.12 Herein the development, scope and limitations
of a-aroyloxyaldehydes, readily prepared from commercially
available starting materials, as alternative precursors for
NHC-promoted redox transformations is detailed (Fig. 1).
Two features were considered in the design of alternative
substrates for NHC-promoted redox processes. Firstly, the
leaving group ability of the a-functional group, and secondly,
the synthetic availability and stability of these substrates.
Scheme 1 a-Benzyloxy and a-phenoxyaldehydes in redox esterifications.
a-Aroyloxyaldehydes were next investigated, as the leaving
group ability of the a-functional group could be readily varied
through appropriate substitution of the aroyl unit. Furthermore,
two simple synthetic routes to these compounds from
commercially available starting materials could be employed.
Based upon Tomkinson’s methodology for the a-oxidation of
carbonyls,14 a series of a-aroyloxyaldehydes was prepared.
Alternatively, a-aroyloxyaldehydes are readily synthesised via
addition of vinyl magnesium bromide to the desired aldehyde
or ketone, O-benzoylation and ozonolysis (Scheme 2). In our
hands these aldehydes are typically stable solids that can be
stored without special precaution.15
Fig. 1 Synthetic precursors for NHC-promoted redox reactions.
EaStCHEM, School of Chemistry, University of St Andrews,
North Haugh, St Andrews, KY16 9ST, UK.
E-mail: ads10@st.andrews.ac.uk
w This article is part of the ‘Emerging Investigators’ themed issue for
ChemComm.
Scheme
2
Synthetic strategies for the synthesis of a-aroyloxy-
Chem. Commun., 2011, 47, 373–375 373
z Electronic supplementary information (ESI) available: Spectro-
scopic details for all compounds. See DOI: 10.1039/c0cc02456b
aldehydes.
c
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The ability of the parent a-benzoyloxyaldehyde 6 to
undergo redox esterification with benzyl alcohol as an external
nucleophile was tested to probe the reactivity of this substrate
class (Table 1). In toluene, using Cs2CO3 as the base,
N-mesityl precatalyst 10 gave improved reactivity in comparison
to N-phenyl analogue 2, although imidazole was required
as an additive to achieve acceptable product conversion
(entries 1–4). Using excess NEt3 led to acceptable product
conversion using N-mesityl precatalyst 10 without the need for
an additive, while N-Ph precatalyst 2 proved unreactive under
these conditions (entries 5–7). Further optimisation probed the
effect of incorporating electron withdrawing NO2 substituents
within the benzoyl group. Under standardised conditions,
redox catalysis using 2-nitrobenzoyloxyaldehyde 7 proved slug-
gish, although improved reactivity was observed with 3- and
4-nitrobenzoyloxyaldehydes (entries 8–10 and 12), and using
THF as solvent (entry 11). With 4-nitrobenzoyloxyaldehyde 9,
Cs2CO3 could be used to good effect, but required imidazole as an
additive to reach quantitative product conversion.
Fig. 2 NHC-promoted redox reactions.
reaction product,16 while tertiary a-aroyloxyaldehyde 24 was
inert to redox esterification (Scheme 3).
Table 1 Optimisation of a-aroyloxyaldehydes for redox esterification
Scheme 3 Limitations of NHC-promoted redox reactions.
To extend the utility of this protocol, further investigation
showed that phenol proved a competent nucleophile for redox
esterification, giving the phenyl ester 25.17 This methodology
allowed a simple redox amidation protocol to be established,
as addition of benzylamine to the crude reaction product gave
amide 26 in 65% overall yield from aldehyde 9 (Scheme 4).
Product
conversiona
Entry
Aldehyde
Salt (mol%)
Base (eq.)
1
2
6
6
6
6
6
6
6
7
8
9
9
9
9
2 (20)
10 (20)
2 (20)
10 (20)
2 (20)
10 (10)
10 (20)
10 (10)
10 (10)
10 (10)
10 (10)
10 (20)
10 (20)
Cs2CO3 (0.18)
Cs2CO3 (0.18)
Cs2CO3 (0.18)
Cs2CO3 (0.18)
NEt3 (1.5)
NEt3 (1.5)
NEt3 (1.5)
NEt3 (1.5)
NEt3 (1.5)
NEt3 (1.5)
NEt3 (1.5)
NEt3 (1.5)
Cs2CO3 (0.18)
42%
57%
64%
81%
0%
48%
80%
20%
79%
58%
87%
498%
498%
3b
4b
5
6
7
8
9
10
11c
12
13b
a
All reaction conversions and product distributions were judged by
b
Scheme 4 Redox amidation with benzylamine.
1H NMR spectroscopic analysis of the crude reaction product. Using
c
1.1 eq. of imidazole as an additive. Using THF (0.1 M) as solvent.
Further preliminary and unoptimised results show that
4-nitrobenzoyloxyaldehydes can be used to generate azolium
enolates in situ. Aldehyde 12 participates readily in an NHC-
promoted formal [4+2] cycloaddition18 with b,g-unsaturated
a-ketoester 27, generating dihydropyranone 28 in 54% yield
(69 : 31 dr)19 (Scheme 5).
The scope of this NHC-promoted redox process was next
evaluated. Using benzyl alcohol, 4-nitrobenzoyloxyaldehydes
9, 12 and 13 containing both linear and b-branched a-alkyl
substituents were readily transformed to their corresponding
benzyl esters in good yield (Fig. 2). Further studies showed
that methanol, ethanol, allyl alcohol, and furfuryl alcohol
were all suitable coupling partners, giving the corresponding
esters in good yields, although cyclohexanol gave poor product
conversion and only a modest isolated yield of ester 19.
Limitations of this process were also identified; notably,
a-phenyl substituted aldehyde 22 underwent preferential
base-catalysed rearrangement to generate 23 as the exclusive
Scheme 5 NHC promoted [4+2] cycloaddition.
c
374 Chem. Commun., 2011, 47, 373–375
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4 A range of NHC promoted redox protocols have been demonstrated.
(a) For the conversion of ynals to a,b-unsaturated esters see:
K. Zeitler, Org. Lett., 2006, 8, 637–640; (b) For the ring expansion
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Fig.
3 Mechanistic proposal for NHC-promoted reactions of
a-aroyloxyaldehydes.
Consistent with related proposals,4–8 our current mechanistic
hypothesis for these transformations requires initial formation
of a Breslow-type intermediate 29 from the reaction of the
NHC and the a-aroyloxyaldehyde, with elimination of the
carboxylate generating enol 30. Tautomerisation of enol 30
leads to acylazolium 32 that can be acylated directly by
alcohols; deprotonation of enol 30 leads to azolium enolate
31, either of which can undergo [4+2] cycloaddition, with
both pathways regenerating the NHC (Fig. 3).
9 P.-C. Chiang, M. Rommel and J. W. Bode, J. Am. Chem. Soc.,
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4-nitrobenzoyloxyaldehydes in asymmetric catalysis.
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The authors acknowledge the Royal Society for a URF
(ADS), the EPSRC (KBL) and the EPSRC National Mass
Spectrometry Service Centre (Swansea).
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15 The ESIz contains full procedures for the preparation of
a-aroyloxyaldehydes; these aldehydes have been stored for up to
3 months without decomposition.
16 Reaction in the absence of triazolium salt 10 gave full conversion to 23.
17 Phenyl ester 25 can be isolated in 40% yield by chromatography.
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see: M. He, G. J. Uc and J. W. Bode, J. Am. Chem. Soc., 2006, 128,
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8418–8420.
19 The relative configuration within 28 was assigned by 1H NMR
spectroscopic analysis in comparison to an analogous p-tolyl
derivative; see ref. 17.
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 373–375 375