A facile, one-pot procedure for the conversion of aromatic aldehydes to esters, as well as thioesters and amides, via acyl hydrazide intermediates

Article abstract of DOI:10.1039/c5ra26842g

Herein we present an efficient method for the synthesis of esters from aromatic aldehydes via readily accessible acyl hydrazides. The developed reaction protocol is shown to be tolerant of a range of aromatic aldehydes, bearing various functionalities, as well as being amenable to the synthesis of thioesters and amides.

Full text of DOI:10.1039/c5ra26842g

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A facile, one-pot procedure for the conversion of aromatic
aldehydes to esters, as well as thioesters and amides, via acyl
hydrazide intermediates
Received 00th January 20xx,
Accepted 00th January 20xx
Antoine Maruani,a Maximillian T. W. Lee,a George Watkins,a Ahmed R. Akhbar,a Henry Baggs,a
André Shamsabadi,a Daniel A. Richardsa and Vijay Chudasama*a
DOI: 10.1039/x0xx00000x
www.rsc.org/
Herein we present an efficient method for the synthesis of esters excess.
from aromatic aldehyes via readily accessible acyl hydrazides. The
developed reaction protocol is shown to be tolerant of a range of
aromatic aldehydes, bearing various functionalities, as well as
being amenable to the synthesis of thioesters and amides.
Esters are one of the most important functional moieties in
organic synthesis. They are abundant in various polymers,
natural products and pharmaceutical agents.1 Classically,
esters have been synthesised via the reaction of carboxylic
acid derivatives (e.g. anhydrides, acyl halides and activated
esters) with alcohols.2 An alternative to this classical approach
is the oxidative esterification of aldehydes via a hemiacetal
intermediate (Figure 1a).3 In this context, metal-mediated
oxidative aldehyde esterifications have been investigated in
great detail.3 Effective conversion of aldehyde to ester has
been achieved by the use of gold,4 rhodium,5 palladium6 and
iron7 catalysts. Whilst successful, these protocols tend to
suffer from limited substrate scope due to harsh reaction
conditions, use of a stoichiometric amount of catalyst and the
high cost of the procedures. However, over the last few
decades, direct transition-metal-free aldehyde esterification
protocols have been reported using oxidants such as iodine,8
N-iodosuccinimide,9 oxone,10 pyridinium hydrobromide
perbromide,11 sodium hypochlorite,12 and hydrogen
peroxide.13 Despite the obvious benefits provided by metal-
free protocols, the developed methods suffer from issues of
hemiacetal instability and most methods to date only provide
access to methyl esters in an efficient manner. Thus, an
intriguing alternative for the direct conversion of aldehydes to
esters is that which does not proceed through a hemiacetal
intermediate. Such protocols have been developed using
N-heterocyclic carbene (NHC) methodologies (Figure 1b).14
Nonetheless, these protocols remain, almost solely, limited to
the use of primary alcohols, which are also employed in large
Figure 1 a-b) Classical methods for the direct conversion of aldehydes
to esters and c) the novel strategy disclosed in this manuscript, which
is also amenable to the synthesis of thioesters and amides.
Recently, a plethora of methods for the efficient and
effective conversion of aldehydes to acyl hydrazides have been
reported.15-26 Moreover, the overall transformation has been
shown to proceed under a wide range of reaction conditions,
in a variety of solvents and with the aldehyde being employed
as the limiting reagent. More recently, Chudasama, Caddick
and co-workers have shown the formed acyl hydrazides to
undergo reaction with Grignard reagents for the efficient
synthesis of ketones.19,21 With the acyl donor ability of acyl
hydrazides in mind, we were intrigued by the possibility of
using acyl hydrazides for the synthesis of esters. Moreover,
with the stability of acyl hydrazides being well documented,
we envisioned from the outset that such a development could
be adapted to the one-pot conversion of aldehydes to esters
via an in situ prepared acyl hydrazide intermediate (Figure 1c).
Our study began by optimising the reaction of acyl
hydrazide 1a with n-butanol 2a (Table 1). Initially, the reaction
was carried out under solvent-free conditions with 5 to 100
equivalents of alcohol and using caesium carbonate as base
(Table 1, Entries 1-4). Complete conversion was observed
a.Department of Chemistry, University College London, 20 Gordon Street, London,
WC1H 0AJ, United Kingdom.
Electronic Supplementary Information (ESI) available: [1H and 13C NMR spectra for
all small molecules]. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
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when the reaction was carried out in a vast excess of alcohol of DMF as solvent actually improved the yield of the
(100 eq.). However, it was clear that the solvent-free transformation from 75% to 89% (Scheme 1).
conditions would not be amenable to the synthesis of esters in
high yields without employing a significant alcohol loading. As
such, a solvent screen was carried out using 5 equivalents of
n-butanol 2a and caesium carbonate as base (Table 1, Entries
5-8). An excellent yield of ester 3aa was observed in DMF.
Moreover, high yield was retained on reducing alcohol
equivalence from 5 through to 1.1. However reducing the
Scheme 1 Reaction of aldehyde 6a with azodicarboxylate
“on water” and in DMF.
7 (1.2 eq.)
equivalents of base or exchanging it for other common bases
(e.g. NEt3, DIPEA) reduced the yield dramatically, except for
when potassium tert-butoxide was employed. The main side-
We next appraised whether a one-pot conversion of
aldehyde 6a to ester 3aa was feasible. To do this, the aldehyde
and azodicarboxylate were reacted in DMF at 21 °C for 24 h,
followed by addition of alcohol and caesium carbonate and
incubation at 21 °C for 16 h; reaction times were optimised by
19F NMR studies. To our delight, after this two-step procedure,
flash column chromatography afforded the desired ester in
74% isolated yield.ǂ Notably, a one-pot procedure where all
reagents were combined from the start was also successful,
albeit in a lower overall yield of 54%.
products identified in the reaction protocol were hydrazide
and acid . Hydrazide is likely to have formed via attack of
the alcohol at the carbamate carbonyl, whereas acid is
4
5
4
5
presumably derived from hydrolysis of hydrazide 1a with
residual water in the alcohol or solvent. We also highlight that
the optimised conditions were not amenable to synthesis of
esters when using aliphatic-based acyl hydrazides.
Scheme 2 One-pot conversion of aldehyde 6a to ester 3aa ǂ
.
Entry Solvent
Basea Time/h 2a/eq Conversion 1a/%b 3aa/%b
1
2
3
4
5
6
7
8
9
10
11
12
13
-
-
-
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
16
16
16
16
16
16
16
16
16
16
16
16
16
100
50
10
5
5
5
100
80
55
30
95
100
75
60
97
94
68
70
95
95
70
44
21
88
94
60
48
91
87
60
58
82
With optimised conditions in hand we took the opportunity
to investigate the applicability of our protocol for the
formation of various esters (Table 2). A range of aromatic
aldehydes (6a-f) and alcohols (2a-h) were appraised under the
developed reaction conditions.
-
NMP
DMF
THF
5
5
CH2Cl2 Cs2CO3
DMF
DMF
DMF
DMF
DMF
Cs2CO3
Cs2CO3
NEt3
DIPEA
KOtBu
Cs2CO3
(0.5 eq.)
Cs2CO3
Cs2CO3
2.5
1.1
1.1
1.1
1.1
Entry
1
Aldehyde 6, R1 =
Alcohol, R2 =
Yield/%
14
DMF
16
1.1
60
47
15
16
DMF
DMF
12
6
1.1
1.1
85
51
71
42
74, 3aa
2a
Table 1 Reaction of acyl hydrazide 1a with alcohol 2a under a range of
conditions. 1 eq. unless otherwise stated in parenthesis. 1H NMR
yield of based on pentacholorobenzene as internal standard.
a
b
6a
6b
2
3
72, 3ba
71, 3ca
2a
2a
Having optimised the conditions for the conversion of an
aromatic acyl hydrazide into an ester, we set about combining
this work with the formation of acyl hydrazides from
aldehydes in a single pot. Previously we have reported a highly
efficient protocol for the conversion of aldehydes to acyl
hydrazides using aerobic C-H activation, which proceeded
successfully “on water”.21,22 However, in view of the fact that
esterification proceeded most efficiently in DMF, we appraised
the reaction of an aldehyde with an azodicarboxylate (for the
formation of an acyl hydrazide) in this solvent. Gratifyingly, use
6c
6d
6e
4
5
72, 3da
67, 3ea
2a
2a
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6
7
72, 3fa
76, 3ab
2a
2b
6f
6a
6a
6a
6a
6a
6a
6a
8
52, 3ac
70, 3ad
76, 3ae
2c
9
2d
10
11
12
13
2e
2f
Scheme 3 One-pot conversion of aldehyde 6a to thioesters
azodicarboxylate and thiols
9 using
7
8.
72, 3af
68, 3ag
76, 3ah
Finally, the developed reaction conditions were trialled for
the formation of amides. To do this, aldehyde 6a was reacted
with DIAD followed by the addition of a collection of primary
and secondary amines in the absence of caesium carbonate.
To our delight, good yields were observed across the series
(Scheme 4). Previously, it has been shown that aliphatic-based
acyl hydrazides undergo efficient amide formation when using
primary amines but the yields were significantly reduced on
application of secondary amines due to nucleophilic attack of
the amine at the carbamate carbonyl (i.e. to form compounds
2g
2h
with alcohols
Table 2 One-pot reaction of aldehydes
6
2
for the
formation of esters
3
.
To our delight, the reaction was tolerant of various
functional groups on the aromatic aldehyde motif, e.g. nitro,
halo, trifluoromethyl, cyano and methyl functionalities (Table
2, Entries 1-6), on reaction with n-butanol 2a. Excellent and
consistent yields were observed across the series, 67-76%.
Moving to the tolerance of the alcohol reagent, alcohols
bearing a range of functional groups (e.g. alkene, alkyne,
of the form of hydrazide 4
).21 In this case however, when using
aromatic aldehydes, and thus in turn aromatic hydrazides, no
sharp decrease in yield was observed (ca. 10% reduction). This
discrepancy is likely to be due to the aromatic acyl hydrazide
residing in a different conformation to an aliphatic analogue,
potentially due to the steric clash of the aromatic group and
the carbamate α- to the amide carbonyl group. The developed
procedure is of appreciable significance as amides are of high
value, particularly in the pharmaceutical industry.29 They are
typically prepared via highly reactive acyl derivatives or from
carboxylic acids using one of several possible coupling
reagents.30 Whilst amides may be prepared from aldehydes,
this typically involves the use of undesirable metals.31 Thus,
the detailed protocol provides an appealingly, simple and
orthogonal route for amide preparation from aromatic
aldehydes with tolerance of primary and secondary amines.
aromatic) were appraised, as well as secondary alcohol 2g
.
Gratifyingly, the optimised reaction conditions, on reaction
with aldehyde 6a, afforded esters in generally good yields
(Table 2, Entries 7-13). Perhaps as expected, due to its reduced
nucleophilicity, the only modest yield was observed upon use
of phenol 2c
.
The reaction protocol was also shown to be amenable to
the synthesis of thioesters. Application of the optimised
reaction conditions for the synthesis of esters to the formation
of thioesters afforded various thioesters in good yields
(Scheme 3). Gratifyingly, primary, secondary and benzylic
thiols were all tolerated under the reaction conditions. This
was particularly pleasing as sulfur-containing motifs are
present in a large number of natural products, biologically
active molecules, and materials.27 Traditional methods for the
construction of thioesters tend to be limited to the reaction of
acyl bromides or chlorides with thiol derivatives.28 This suffers
from limitations in terms of the instability and moisture-
sensitivity of acyl bromides/chlorides. Thus, the method
presented is a mild and efficient alternative to traditional
methods, and moreover, may proceed via conversion from an
aromatic aldehyde in a simple one-pot procedure.
Scheme 4 One-pot conversion of aldehyde 6a to amides 11 using
azodicarboxylate 7 and amines 10.
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Conclusions
In conclusion, we have shown readily accessed acyl hydrazides
to be suitable candidates for the synthesis of esters, thioesters
and amides. Moreover, one-pot transformations from
aromatic aldehydes to esters, thioesters and amides have been
established with various aromatic aldehydes, alcohols, thiols
and amines being tolerated under the mild reaction
conditions.
Acknowledgements
The authors gratefully acknowledge Prof. Alwyn Davies for
productive discussions. We also acknowledge UCL (UCL
Excellence Fellowship) for funding.
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ǂ
74% yield refers to the reaction being carried out on a
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Table of Contents Entry
A facile, one-pot procedure for the conversion of aromatic aldehydes to esters, as well as
thioesters and amides, via acyl hydrazide intermediates.