Scandium triflate catalyzed ester synthesis using primary amides

Article abstract of DOI:10.1016/j.tetlet.2014.10.124

A scandium triflate (ScOTf)₃ catalyzed methodology has been developed to synthesize esters from primary amides. Various primary and secondary aliphatic alcohols have been shown to react in n-heptane with a range of primary amides for 24 h.

Full text of DOI:10.1016/j.tetlet.2014.10.124

Tetrahedron Letters xxx (2014) xxx–xxx
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Tetrahedron Letters
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Scandium triflate catalyzed ester synthesis using primary amides
⇑
Benjamin N. Atkinson , Jonathan M. J. Williams
Department of Chemistry, University of Bath, Claverton Down, Bath BA2 7AY, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
A scandium triflate (ScOTf)3 catalyzed methodology has been developed to synthesize esters from pri-
mary amides. Various primary and secondary aliphatic alcohols have been shown to react in n-heptane
with a range of primary amides for 24 h.
Ó 2014 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/3.0/).
Received 17 September 2014
Revised 10 October 2014
Accepted 22 October 2014
Available online xxxx
Keywords:
Amides
Alcohols
Scandium
Esters
Alcoholysis
Amide bonds are robust and thermodynamically stable chemi-
cal moieties due to resonance of nitrogen with the carbonyl.1 How-
ever, despite their inherent chemical inertness amides have gained
popularity as acyl donors by providing alternative synthetic routes
toward acyl derivatives. Transamidation reactions, the direct sub-
stitution reaction of an amide with an amine, have received sub-
stantial interest from a number of groups,2 including our own.
This has led to the broadening of reactivity scope as well as an
increase in the variety of catalysts used including metals,3 non-
metals,4 and organocatalysts,5 as well as stoichiometric amounts
of promoters.6
Direct alcoholysis of amides with alcohols has been carried out
using three main methods. The first method is the direct activation
of an amide using activating agents, early examples used silicon or
boron fluorides.7 More recent examples used stoichiometric
amounts of activating agents such as amide acetals (dimethylform-
amide dimethyl acetal),8 tellurium ethoxide,9 phosphates,10 or tri-
flic anhydride based protocols.11 Other methods used a titanium
catalyst and required a stoichiometric amount of hydrochloric
acid.12 The second method uses twisted amides to increase the sus-
ceptibility of the amide to nucleophilic attack via disruption of the
amide bond resonance.13 The third method uses directing-group-
assisted activation of the amide bond, this ligand-like binding of
an intramolecular heteroatom increases the susceptibility of the
carbonyl toward nucleophilic attack.14 However, in all cases, stoi-
chiometric activators or tailored substrates were necessary. Mashi-
ma recently described an excellent and simple cooperative
catalytic system using scandium triflate in combination with a
boronic ester for the alcoholysis of a non-activated amide, how-
ever, a large excess of alcohol was required.15 As such, we chose
to investigate a general, metal-catalyzed methodology for the alco-
holysis of amides not requiring the alcohol substrate as the reac-
tion solvent.
Identification of a suitable catalyst began by examining the
alcoholysis, at 10 mol % loading, of n-hexanamide (1) with benzyl
alcohol (2) (Table 1). Our choice of catalyst was influenced by pre-
vious work investigating the activation of amides using zircono-
cene dichloride (Cp2ZrCl2).3h Only Sc(OTf)3 showed catalytic
activity for the alcoholysis reaction (entry 3), with no activity seen
with Cp2ZrCl2 or a titanium-based catalyst (entries 1 and 2).
Increasing the temperature and reducing the catalyst loading gave
89% conversion into the ester 3a (entry 4). Little or no catalytic
activity was observed with other lanthanide triflates or with
Mg(OTf)2 (entry 5).16 Only 23% conversion into ester 3a was
observed using triflic acid (15 mol %) (entry 6), highlighting the
reaction dependence on Sc(OTf)3. Increasing the concentration
and equivalents of alcohol lowered the overall conversion, albeit
marginally with regard to the equivalents of alcohol.16
Sc(OTf)3 is known to be a water tolerant Lewis acid catalyst,17
and we therefore investigated the tolerance of the reaction toward
the presence of water. Interestingly, the use of anhydrous Sc(OTf)3
in combination with anhydrous n-heptane resulted in reduction in
the overall conversion to 80%.16 Conversely, increasing the amount
of water present did not increase conversion into the ester product,
with 74% conversion seen with two equivalents of water present
(entry 7).16
⇑
Corresponding author.
E-mail address: b.n.atkinson@bath.ac.uk (B.N. Atkinson).
http://dx.doi.org/10.1016/j.tetlet.2014.10.124
0040-4039/Ó 2014 The Authors. Published by Elsevier Ltd.
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).
Please cite this article in press as: Atkinson, B. N.; Williams, J. M. J. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.10.124

2
B.N. Atkinson, J.M.J. Williams / Tetrahedron Letters xxx (2014) xxx–xxx
Table 1
Table 2
Alcoholysis scope using n-hexanamidea
Catalyst identification and reaction optimization
anhydrous
Sc(OTf)3 (5 mol%)
n-heptane (1.0 M)
O
cyclohexane
O
O
O
or n-heptane
R
R
n
Pent
NH2
HO
Ph
n
Pent
O
Ph
n-Pent
NH2
n-Pent
O
HO
1.2 equiv
100 oC, 24 h
24 h
1
2
3a
3a-k
1.2 equiv
Entry
1
Product
Yieldb (%)
Entry
Catalyst (mol %)
Temp (°C)
Yielda of 3a (%)
O
3a
90 (98)
1
2
3
4
5
6
7
8
Ti(Oi-Pr)4 (10)
Cp2ZrCl2 (10)
Sc(OTf)3 (10)
Sc(OTf)3 (5)
Mg(OTf)2 (5)
TfOH (15)
80
80
80
100
100
100
100
100
0
0
n-Pent
n-Pent
O
O
Ph
53
89
0
23
74b
98c
O
3b
83 (92)
2
3
C6H44-Cl
O
O
3c
48 (53)
Sc(OTf)3 (5)
Sc(OTf)3 (5)
n-Pent
n-Pent
O
O
C6H44-NO2
3d
74 (80)
a
b
c
Conversions calculated by analysis of the crude 1H NMR spectra.
Carried out with two equivalents of H2O.
Carried out in reagent grade solvent and in an open reaction vessel.
O
O
4
O
O
O
3e
93 (99)
5
6
n-Pent
n-Pent
n-Pent
O
O
O
2-Naphth
3f
91 (98)
Interestingly, throughout the optimization process, no symmet-
rical ether (dibenzyl ether) formation was observed.18 Additionally,
no benzylated amide products or n-hexanoic acid were observed.
Using our optimized conditions (Table 1, entry 8) with Sc(OTf)3
(5 mol %), we went on to explore the substrate scope of this
reaction with respect to the alcohol (Table 2).
nHept
3g
82 (87)
7
Ph
O
O
3h
85 (93)
8
9
Alcoholysis of n-hexanamide with a variety of benzyl alcohols
afforded the corresponding esters in moderate to excellent yields.
Electron-withdrawing groups on the aryl ring gave reduced yields
of products, likely due to the reduced nucleophilicity of the alcohol
(entries 2 and 3). With electron-rich alcohols it was seen that a
significant amount of the symmetrical ether was observed, notably
with 4-methoxybenzyl alcohol only 55% conversion into product
was observed and 13% conversion into symmetrical ether.
However piperonyl alcohol gave a much cleaner reaction with only
2% of the symmetrical ether observed (entry 4). The straight chain
alcohol n-octanol reacted cleanly to give 91% yield (entry 6). Other
alcohols such as 3-phenylpropyn-1-ol and geraniol reacted cleanly,
giving the corresponding esters in high yields without ether
formation (entries 7 and 8).
n-Pent
n-Pent
O
O
3i
À(34)
84 (90)c
3j
72 (80)c
O
O
10
11
n-Pent
n-Pent
O
O
3k
83 (88)c
Ph
a
Reactions performed on 2 mmol scale with 2.4 mmol of alcohol in 2 mL of
solvent.
b
Isolated yield; figures in parentheses are conversions determined by analysis of
the 1H NMR spectra.
c
Reaction carried out at 125 °C in n-octane.
Unfortunately, cyclohexanol only gave 34% conversion into the
ester at 100 °C (entry 9). However, simply increasing the tempera-
ture to 125 °C for this substrate and for other secondary alcohols
resulted in good yields of ester products (entries 9–11), for both
acyclic and cyclic secondary alcohols. L-Menthol reacted cleanly
giving the ester product (entry 10) whilst maintaining the enantio-
meric purity (>99% ee by HPLC). When secondary benzylic alcohols
were used, such as 1-phenylethanol, a significant amount of sym-
metrical ether was observed.19 It was noted that even at 125 °C no
reaction occurred under optimized reaction conditions (Table 2),
between phenol and n-hexanamide.
Alcoholysis of primary amides was also investigated using
benzyl alcohol (Table 3). 2-Phenylacetamide reacted cleanly to give
a 90% yield of ester product (entry 1). Alkyl halides were also
tolerated; 2-chloropropionamide gave a modest yield of 55% of
the corresponding benzyl ester (entry 2). Higher temperatures
were required for less reactive amides, however good yields of
78% and 71% were obtained for both benzamide and thiophene-
2-carboxamide (entries 3 and 4, respectively). Even at these higher
temperatures, only a 39% yield of benzyl pivalate was obtained
(entry 5). Secondary and tertiary amides, specifically N-methylac-
etamide and N,N-dimethylacetamide, showed no reaction with
benzyl alcohol at 125 °C, highlighting the specificity of the reaction
toward primary amides.
On reaction of ethyl hydrocinnamate and 2-phenylacetamide with
one equivalent of benzyl alcohol an 89% total conversion into
benzyl ester products was observed (Scheme 1). Of the converted
starting materials, a 61:39 ratio of alcoholysis product (4a) to
transesterified product (4f) was seen indicating the greater reactiv-
ity of the amide over the ester. Interestingly, although a lower total
conversion of 67% was observed, esterification of the hydrocin-
namic acid proceeded more quickly than the alcoholysis of the
primary amide with an observed ratio of 24:76 (4a:4f).
The use of symmetrical aryl ether 5 in the reaction did not yield
any ester product (Scheme 2). Even with 0.5 equiv of water
present, no reaction was seen indicating that the reaction pathway
did not proceed via ether formation and subsequent
fragmentation.
To a 1:1 mixture of n-hexanamide–n-octanol in CDCl3 at 30 °C,
increasing amounts of Sc(OTf)3 were added. Analysis of both the 1H
and 13C NMR spectra showed a downfield shift of both the NH
amide signals, in the 1H NMR, and the carbonyl signal in the 13C
NMR, clearly indicating coordination to the scandium atom
(Table 4). As such, a mechanism analogous to that of the Fischer
esterification of carboxylic acids is proposed, via activation of the
amide to nucleophilic attack through carbonyl coordination. The
significantly low solubility of ammonia in the reaction solvent, as
Competition reactions were carried out to determine the reac-
tivity in comparison with carboxylic acids and esters (Scheme 1).
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B.N. Atkinson, J.M.J. Williams / Tetrahedron Letters xxx (2014) xxx–xxx
3
Table 3
Table 4
Alcoholysis scope using benzyl alcohola
NMR data for Sc(OTf)3 binding to n-hexanamidea
1H NMR
13C NMR
Sc(OTf)3 (5 mol%)
n-heptane (1.0 M)
O
O
Sc(OTf)3 (mol %)
HO
Ph
NH shifts (ppm)
a
-CH2 shift (ppm)
C@O shift (ppm)
R
O
Ph
R
NH2
100 oC, 24 h
1.2 equiv
4a-e
0
5
10
6.22 (2H)
6.86, 6.49
7.37, 6.78
2.10
2.15
2.19
176.79
177.79
178.70
Entry
1
Product
Yieldb (%)
a
Conditions: n-hexanamide (0.6 mmol), n-octanol (0.6 mmol), CDCl3 (0.6 mL),
O
4a
90 (99)
25 °C, 400 MHz.
Ph
O
Ph
O
4b
55 (59)
2
3
O
Ph
reactivity, under these conditions, toward nucleophilic acylation
reactions of primary amides rather than esters. Mechanistic studies
revealed the activation of the primary amide by scandium, as
demonstrated by analysis of both 1H and 13C NMR spectra.
Cl
O
4c
À(23)
Ph
O
O
Ph
78 (82)c
4d
71 (78)c
4
5
Acknowledgements
O
Ph
S
O
4e
We thank the EPSRC for funding and the University of Bath for
further support.
39 (46)c
tBu
O
Ph
a
Reactions performed on 2 mmol scale with 2.4 mmol of alcohol in 2 mL of
solvent.
Supplementary data
b
Isolated yield; figures in parentheses are conversions determined by analysis of
the 1H NMR spectra.
Supplementary data (experimental details, optimization reac-
tions, characterizations and spectroscopic data) associated with
this article can be found, in the online version, at http://
dx.doi.org/10.1016/j.tetlet.2014.10.124.
c
Reaction carried out at 125 °C in n-octane.
O
O
Sc(OTf)3 (5 mol%)
benzyl alcohol (1.0 mmol)
Ph
Ph
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100 oC, 24 h
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O
n-heptane (1.0 M)
100 oC, 24 h
67% total
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Ph
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conversiona
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Scheme 1. Competition reactions with carboxylic acids and esters. aConversion
determined by analysis of the crude 1H NMR spectra.
Sc(OTf)3 (5 mol%)
H2O (0.5 mmol)
O
O
n-Pent
NH2
n-Pent
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4
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Please cite this article in press as: Atkinson, B. N.; Williams, J. M. J. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.10.124