Amyl nitrite-mediated conversion of aromatic and heteroaromatic primary amides to carboxylic acids

Article abstract of DOI:10.1016/j.tetlet.2015.05.054

A series of aromatic and heteroaromatic primary amides were converted directly to carboxylic acids by heating with amyl nitrite in acetic acid. Most conversions proceeded to give reasonable to excellent yields on a range of substrates containing various functional groups. This reagent system is thus applicable for the direct hydrolysis of a range of different primary carboxamides. The reaction with a phenolic aromatic substrate afforded two alternative nitration products as major outcomes, evidencing alternative reaction pathways resulting from the free phenolic OH.

Full text of DOI:10.1016/j.tetlet.2015.05.054

Accepted Manuscript
Amyl nitrite-mediated conversion of aromatic and heteroaromatic primary
amides to carboxylic acids
Garrett T. Potter, Gordon C. Jayson, Gavin J. Miller, John M. Gardiner
PII:
S0040-4039(15)00863-1
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.05.054
TETL 46326
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
24 December 2014
2 April 2015
18 May 2015
Please cite this article as: Potter, G.T., Jayson, G.C., Miller, G.J., Gardiner, J.M., Amyl nitrite-mediated conversion
of aromatic and heteroaromatic primary amides to carboxylic acids, Tetrahedron Letters (2015), doi: http://
dx.doi.org/10.1016/j.tetlet.2015.05.054
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Amyl nitrite-mediated conversion of aromatic and
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Garrett T. Potter, Gordon C. Jayson, Gavin J. Miller and John M. Gardiner

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Amyl nitrite-mediated conversion of aromatic and heteroaromatic primary amides to
carboxylic acids
a
Garrett T. Potter, Gordon C. Jayson, Gavin J. Miller and John M. Gardiner
b
c
a*
a
Manchester Institute of Biotechnology, School of Chemistry, Faculty of EPS, The University of Manchester 131 Princess Street, Manchester M1 7DN, UK.
Institute of Cancer Sciences, The University of Manchester, Wilmslow Road, Manchester M20 4BX, UK.
School of Chemistry, Faculty of EPS, The University of Manchester, Oxford Road, Manchester M13 9PL, UK.
b
c
ARTICLE INFO
ABSTRACT
Article history:
Received
A series of aromatic and heteroaromatic primary amides were converted directly to carboxylic
acids by heating with amyl nitrite in acetic acid. Most conversions proceeded in reasonable to
excellent yield on a range of substrates containing various functional groups. This reagent
system is thus applicable for the direct hydrolysis of a range of different primary carboxamides.
The reaction with a phenolic aromatic substrate afforded two alternative nitration products as the
major outcomes, evidencing alternative reaction pathways resulting from the free phenolic OH.
Received in revised form
Accepted
Available online
Keywords:
2009 Elsevier Ltd. All rights reserved.
Primary Amide
Carboxylic acid
Nitration
Diazotization
1
. Introduction
____________________________________________________
1d
Although there have been advances in ester hydrolysis, Figure
summarizes a range of reagents previously employed to effect
2-5
The transformation of primary amides into carboxylic acids is
1
direct primary amide hydrolysis. Several of these methods
frequently required in organic synthesis. Classical approaches
necessitate strongly acidic or alkaline conditions. Due to the
forcing nature of these conditions and limitations on functional
group compatibility, there is an ongoing interest in developing
alternative reagents for primary amide hydrolysis that are
involve multiple steps, via intermediates, reducing the overall
5a
efficiency. For example conversion to an acyl pyrrole which
can then undergo methanolysis, conversion to a bis-carbamate
5b
with subsequent mildly basic hydrolysis, and conversion to an
compatible with
a wider range of other functionalities.
Biocatalytic amide hydrolysis is widely employed, though
N-acyl phthalimide with succinic anhydride and subsequent
5c,d
hydrolysis.
synthesis of
As part of a program to develop a scalable
6
L-iduronic acid-containing carbohydrates, we
1
a-f
synthetic examples using primary amides are few.
required mild reaction conditions for the transformation of L-
iduronamide 1 into -iduronic acid 2 (Scheme 1). Of particular
L
7
interest was the potential use of nitrosyl type reagents. Amyl
nitrite (isopentyl nitrite) is a mild, non-toxic reagent, which we
found to be effective for the conversion of primary amide 1 into
carboxylic acid 2 in good yield. This reaction could be scaled to
produce >50 g batches of the desired acid 2 in good yields and
was tolerant of acetal, acyl and benzylic ether protecting groups.
N
OH OAc
O
O
OH OAc
AcOH, 80-100 °C
69%
H
2
NOC
O
OAc
HO
2
C
O
OAc
OBn
OBn
1
2
Figure 1. Summary of reagents used to convert primary amides
to carboxylic acids in one step or via isolated amide-derived
6
Scheme 1. Conversion of L-iduronamide 1 into acid 2.
2
-5
intermediates.
*Corresponding author. Tel +44 (0)161 306 4530; e-mail: gardiner@manchester.ac.uk

2
Tetrahedron
This was also found to be applicable to the analogous
Although the amyl nitrite-mediated conversion proved
applicable to all primary amides tested, there were significant
differences in yields obtained, and in one case two major
alternative side-products/reactions were evident, accounting for
the low isolated yield of the anticipated carboxylic acid product.
glucuronamide providing a route to glucuronic acids, so we
sought to evaluate the scope of this reagent for the conversion of
non-carbohydrate primary amides to carboxylic acids. We report
herein the compatibility of this reagent system for the hydrolysis
of a range of aryl (Table 1) and heteroaryl primary amides (Table
Steric and electronic effects may influence some of these
differences. Direct comparison of p-nitro benzamide (7, isolated
in 57% yield) against o-nitro benzamide (2, isolated in 31%
yield) could be accounted for by steric influences. In general, p-
substituted benzamides (6, 8, 9 and 11) were good substrates (all
were isolated in >85% yield) whilst the o-Me substituted (3, 50%
yield) and doubly m-OMe substituted amides (5, 33% yield),
were significantly poorer substrates. However, proposing an
2
).
2. Results and Discussion
A diversity of aromatic and heteroaromatic substrates were
considered for evaluation which encompassed a range of
different electron withdrawing and donating groups, different
regiochemistry of substituents and fused aryl and heteroaryl
variants.
6
acylium intermediate for this type of reaction, is not consistent
with electronic effects, since a p-trifluoromethyl substrate was
also converted in high yield.
Table 1
Conversion of aromatic primary amides to carboxylic acids
Table 2
Conversion of heteroaromatic primary amides to carboxylic
acids
a
Entry
1
Aromatic amide
Carboxylic acid
% Yield
Heterocyclic
amide
Heterocyclic
carboxylic acid
a
Entry
1
% Yield
b
c
3
50
b
12
13
98
2
3
4
5
31
O
NH2
N
c
2
3
53
Cl
d
33
b
14
15
30
d
e
4
5
6
7
8
6
94
b
4
47
7
57
a
b-c
Isolated yield. Reaction time (h): =24, =6
b
c
d
86
For the selected series of heteroaromatic substrates covering
pyridine, xanthene and benzothiophene examples (Table 2,
entries 2-4), the yields were generally modest (compounds 13, 14
and 15 all formed in >30%). However, a 3-substituted pyridine
8
b
94
(entry 1, Table 2) proved a very effective substrate (98% isolated
yield of 12).
9
f
10
11
13
90
f
9
a
Isolated yield.
b-f
Reaction time (h): =12, =13, =24, =6, =21
b
c
d
e
f
Scheme 2. Formation of nitrated side-products 16 and 17.

3
1
Figure 2. H NMR (400 MHz) monitoring of the reaction to form 10, 16 and 17.
Of particular note was the low isolated yield
substituted benzoic acid 10. This was dramatic
the outcome with related p-anisole derivative wh
(
(
13%) of p-OH
effected by prolonged heating in neat AcOH. However,
additional experiments heating isolate 16 in AcOH showed no
aa lly different to
dd
ere the expected
conversion to 17, supporting a need for amyl nitrite and perhaps
an alternative m-nitration mechanism .. Further investigation of
this nitration process is currently under ww ay.
hydrolysis product 9 was obtained in 94% yield. Further
investigation of this reaction established that two other by-
products accounted for the low isolated yield (Sc
h
h
eme 2).
3. Conclusions:
These were identified as m- and o-nitro sub
acids, 16 and 17 respectively, each obtained in si
ss tituted benzoic
milar quantities
m
We have investigated the applic aa tion of a commercially
available, non-toxic reagent, amyl nitrite, for a mild conversion
8
of around 40%.
of primary aromatic and heteroaromat ii c amides into carboxylic
acids. Whilst yields are varied and dependent on the aryl or
heteroaryl substitution, this work clearly indicates that amyl
nitrite/AcOH should be considered as aa viable reagent system for
t
BuONO has previously been used as
a mild and
chemoselective method to nitrate phenols, and the formation of
6 could occur via a similar process involving eneration of a
phenolic -nitroso intermediate and subsequ nt -nitration
suggested to occur through phenoxide radical/N
This prior work reported that anisole substrates
aromatic nitration, which is consistent with our outcome here,
and thus indirectly is in support of proposing amy nitrite forming
an initial reactive intermediate with the free phen l.
1
gg
O
e
O
C
effecting primary amide hydrolysis, no tt just in carbohydrates but
9
(
2
generation).
in a broader range of aromatic and heteroaromatic systems. We
have also observed and isolated two nit rr ation by-products using a
phenolic substrate. This established phenolic o-nitration as the
kinetic product and that this is converted on prolonged heating,
dependent on the presence of amyl nitrite, to the m-nitrated
phenol.
ww ere resistant to
ll
oo
Whilst this mechanism could account for the formation of 16,
we were also interested in the formation of the m jor by-product,
7. We followed the progress of the reactio to track the
formation of 17 using H NMR spectroscopy (Figure 2). The
results from this study demonstrated that 17 wa formed as the
thermodynamic product of the reaction after prol nged heating in
aa
Acknowledgements:
1
nn
1
The MRC [G0601746 and G90217 33 ] are thanked for project
grant funding and the Paterson Ins tt itute for supplementary
stipend support (to G.T.P.). The EPSRC National Mass
Spectrometry Service, Swansea are also thanked for mass
spectroscopic analyses.
s
o
neat AcOH (24 h) and that the kinetic product of nitration, under
our conditions, was 16.
The mechanism for the conversion of 16 to 11 7 is not clear.
There is precedent for homoaromatic 1,2 or 1,4 migration of nitro
Supplementary Material
1
0
groups (through Wheland-type intermediates),
which could be

4
Tetrahedron
Supplementary data (representative experimental
procedures, characterization data, and copies of NMR) associated
with this article can be found, in the online version, at http://….
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8
.
4-Hydroxybenzoic acid (10): 4-hydroxybenzamide (137 mg, 1.0 mmol)
was dissolved in acetic acid (2.0 mL), and to this stirred solution was
2
added amyl nitrite (0.40 mL, 3.0 mmol) under a N atmosphere and
heated to 80 °C for 21 hours, whereupon the reaction was deemed
complete as adjudged by consumption of starting material by TLC. The
solution was condensed, co-evaporated with toluene (2 x 5 mL) and then
purified via preparatory plate TLC. Sections containing product and by-
products were scraped, extracted into EtOAc and solvent removed in
vacuo. This yielded two separate fractions. A: 95.8 mg of a light yellow
powder which was an inseparable mixture of 10 (0.13 mmol) and 17
(
1
0.43 mmol), as adjudged by H NMR analysis; R
f
= 0.68 (50% EtOAc in
1
Hexane); For 10: H NMR (400 MHz; MeOD): δ 8.02 (d, J = 9.2 Hz,
-
1
H), 6.79 (d, J = 9.2 Hz, 2H); MS m/z 138.0 (M , 100%); For 17: H
2
NMR (400 MHz; MeOD): δ 8.58 (s, 1H), 8.09 (d, J = 7.1 Hz, 1H), 7.09
-
d, J = 7.1 Hz, 1H); MS m/z 182.0 (M , 100%). B: 71.0 mg of a yellow
(
powder 16 (0.39 mmol); R
1
= 0.24 (50% EtOAc in Hexane); H NMR
f
(
1
400 MHz; MeOD) δ 8.66 (d, J = 2.2 Hz, 1H), 8.12 (dd, J = 8.8, 2.2 Hz,
-
H), 7.23 (d, J = 8.8 Hz, 1H); MS m/z 181.0 (M , 100%); m.p. 184-187
°C; IR (neat) νmax 3289 (br, O-H stretch), 1662 (s, C=O stretch), 1627
(C=C), 1538 (nitro, asymmetric), 1326 (nitro, symmetric), 1258 (acyl C-
O) cm .
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