A catalytic and tert-butoxide ion-mediated amidation of aldehydes with para-nitro azides

Article abstract of DOI:10.1039/c3cc40452h

We report here a new catalytic reaction in which, para-nitro azides are acylated by aldehydes to produce amides and molecular nitrogen in a single step. The transformation is believed to proceed via an electron transfer process mediated by the tert-butoxide ion, and catalysed by a thiazolium salt derived species. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c3cc40452h

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A catalytic and tert-butoxide ion-mediated amidation
of aldehydes with para-nitro azides†
Cite this: Chem. Commun., 2013,
49, 2759
Giorgio Carbone, James Burnley and John E. Moses*
Received 18th January 2013,
Accepted 12th February 2013
DOI: 10.1039/c3cc40452h
www.rsc.org/chemcomm
We report here a new catalytic reaction in which, para-nitro azides
are acylated by aldehydes to produce amides and molecular nitrogen
in a single step. The transformation is believed to proceed via an
electron transfer process mediated by the tert-butoxide ion, and
catalysed by a thiazolium salt derived species.
Scheme 1 A proposed mechanism to explain the catalytic reduction of 1 to
aniline 4 by the tert-butoxide ion.
Amide bond forming reactions are among the most executed in
organic chemistry, forming key linkages in peptides, proteins,
synthetic polymers and drugs.1 Traditional approaches to amide
synthesis involving the coupling of activated carboxylic acid or coupling reagents has been investigated.10,11 The mechanism
derivatives (anhydrides and acyl chlorides) with nucleophilic is believed to involve the nucleophilic attack of the thioacetate
amines are expensive, wasteful and often produce toxic by-products onto the azide N-3 followed by formation of a cyclic thiatriazoline
necessitating lengthy purification.2 The demand for sustainable intermediate, which collapses to give the amide, nitrogen gas
and greener3 approaches to amide synthesis has stimulated intense and elemental sulfur.11 In seeking to further develop the theme
activity in the development of new and creative catalytic methods.1d of this chemistry, we were intrigued by the possibility of using
Straightforward and desirable methods involving the direct aldehydes directly in a redox azido-amidation type-process, thus
coupling of carboxylic acids and amines with certain boronic broadening the range of available substrates and eliminating the
acid catalysts have been reported.4 Other strategies generally sulfur by-product.
involve either the catalytic or oxidative acylation of an amine, or
In recent studies, we observed that in the presence of the
occur by a suitable combination of complementary reaction partners thiazolium salt (2), the tert-butoxide ion selectively reduces
following a unique pathway. For example, the generation of activated the azide group of 1-azido-4-nitrobenzene (1) (Scheme 1).12
carboxylates from functionalised aldehydes by N-heterocyclic The reaction is believed to proceed by an electron transfer
carbene (NHC) catalysts with a co-catalyst, followed by their conver- process via the dianion 3, followed by concomitant loss of
sion to amides has been shown to work with a variety of amines.5 nitrogen gas to give aniline 4.
Oxidative processes utilising NHC’s6 and metal based catalysts have
We now report the tert-butoxide ion mediated amidation of
been used for amide formation from aldehydes with stoichiometric aldehydes13 with para-nitro azides, catalysed by a thiazolium
oxidants.7 The ruthenium catalysed conversion of alcohols and salt derived catalyst. This clean transformation allows the
primary amines with loss of H2 developed by Milstein et al.8 synthesis of para-nitro aromatic amides in one step with high
represents an example of an atom economic and green approach atom economy, and driven by loss of environmentally benign
to amide synthesis, whereas the oxidative coupling of a-bromo nitrogen gas.14
nitroalkanes with amines offers a quite different pathway.9
For the reaction development we opted to use the electron
The formation of amides by the intermolecular coupling of deficient 1-azido-4-nitrobenzene (1), with benzaldehyde (5) as the
thioacids and electron poor anilines that require no activating acyl donor. Using previously optimised conditions for the azide-
reduction as a starting point (2 equiv. tert-BuONa, THF, rt),12
a
number of preliminary reactions were performed (Table 1).
School of Chemistry, University of Nottingham, England, UK NG7 2RD.
E-mail: john.moses@nottingham.ac.uk; Tel: +44 (0)115 951 3533
† Electronic supplementary information (ESI) available: Full experimental proce-
dures and characterisation with 1H and 13C NMRs and schemes referenced in the
text. See DOI: 10.1039/c3cc40452h
Thus, treatment of the azide 1 and aldehyde 5 in THF with
tert-BuONa at room temperature immediately resulted in the
evolution of a gas and, complete conversion of the starting
material 1. After chromatography, the corresponding target
c
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Table 1 Optimisation of the reaction conditions and control experiments
Table 2 Reaction of para-nitro aromatic azides with various aldehydes
Entry
1
Aniline
Aldehyde
Amide
Yielda (%)
94
Entry 2 (equiv.) Base (equiv.) T (1C) 6 yielda (%) 4 yielda (%)
1
2
3
4
5
6
7
—
—
1.0
—
1.0
0.1
0.1b
NaOtBu (2.0) rt
56
51
30
0
80
81
83
39
36
62
0
0
0
KOtBu (2.0)
rt
NaOtBu (3.0) rt
NaOtBu (2.0) À25
NaOtBu (3.0) À25
NaOtBu (2.0) À25
NaOtBu (2.0) À25
2
3
4
5
85
77
84
91
0
a
b
Isolated yield after chromatography. 2 added after stirring a mixture
of 1 and 5 at À25 1C in the presence of tert-BuONa.
amide 6 was isolated in 56% yield along with para-nitroaniline
(4) (39%) (Table 1, entry 1). Similar results were achieved when
the potassium salt of tert-butoxide ion was employed; giving
amide 6 (51%) and aniline 4 (36%) (Table 1, entry 2). However,
when the same reaction was carried out in the presence of
1 equiv. of the thiazolium salt 2, the yield of the amide 6
decreased (30%) whereas the aniline 4 was isolated in higher
yield (62%) (Table 1, entry 3).
When a solution of 1 and 5 was treated with tert-BuONa
(2 equiv.) at À25 1C without catalyst, unreacted starting materials
were recovered (Table 1, entry 4). In contrast, the addition of 2
(1 equiv.) to the reaction mixture at À25 1C followed by tert-
BuONa (3 equiv.) gave the target amide 6 in 80% yield with no
observed aniline 4 (Table 1, entry 5). A reduced loading of 2
(0.1 equiv.) resulted in a similar yield of the amide 6 (81%)
(Table 1, entry 6).
Stirring a mixture (30 min) of the azide 1, the aldehyde 5 and
tert-BuONa (2 equiv.) at À25 1C; no reaction was observed (TLC)
until the addition of 2 (0.1 equiv.), then after a further 30 min,
the amide 6 was isolated in 83% yield (Table 1, entry 7).
We next investigated the one pot diazotisation–azidation–
amidation reaction, since this would negate the isolation of the
azide substrate.15 This proved viable; the diazotisation/azidation
of para-nitroaniline 4 with tert-BuONO/TMSN3 at 0 1C in THF,16
followed by catalytic amidation at À25 1C provided the amide 6
in an excellent 94% yield (Table 2, entry 1). The scope of the
tandem reaction was next investigated with a number of electron
deficient anilines and several aldehydes (Table 2, entries 1–15).
6
7
8
79
89
38
9
82
94
88
10
11
12
13
78
92
Both ortho- and meta-substituents on the para-nitroaromatic 14
azide were well tolerated with benzaldehyde (5) (Table 2,
83
87
entries 2–4). The reaction worked well when electron deficient
15
anilines were coupled with electron rich aromatic aldehydes,
including ortho- and para-substitution on the aromatic aldehyde
(Table 2, entries 5–7).
a
Isolated yield after chromatography.
When an electron deficient aromatic aldehyde was used, the
yield of amide dropped significantly (38%) (Table 2, entry 8).
The reaction raises a number of interesting questions
The heteroaromatic thiophene-2-carbaldehyde was tolerated, with regard to the mechanism. During the 1980’s, Guthrie
giving the corresponding amide isolated in good yield (82%) and co-workers published a number of detailed papers on the
(Table 2, entry 9). When aliphatic aldehydes were employed; reaction mechanism between the tert-butoxide ion and nitro-
high yields were consistently obtained (78–94% yield, benzene, involving SET processes.17 Indeed, the function of tert-
entries 10–15).
butoxide ion as an electron transfer agent is well documented.18
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In summary, we have documented a new and straightforward
synthetic method for the catalytic synthesis of substituted para-
nitroaromatic amides, based upon an azido-amidation mecha-
nism. This method offers an orthogonal approach to current
methodology and, in particular, the method works particularly
well with electron deficient anilines, thus complementing
existing methodologies involving activated carboxylic acid
derivatives. Studies are currently ongoing to unravel the mecha-
nistic details of the reaction.
Scheme 2 Subjecting the triazene 7 to the preferred amidation conditions did
not lead to the formation of 6.
We thank the University of Nottingham, Amity University
and EPSRC (EP/I028951/1) for funding.
Notes and references
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Scheme 3 A plausible amidation mechanism from 1 (R = Ph).
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When the amidation reaction of the azide 1 and benzaldehyde
(5) was attempted under an atmosphere of oxygen or in the
presence of the radical trap TEMPO,19 no reaction was observed
with complete recovery of the azide 1. These results, which are
consistent with our earlier findings12 provide support for a radical
based mechanism in the amidation process (see Scheme S1, ESI†).
The relative nitrogen connectivity between the starting azide
and the corresponding amide was determined by performing
experiments with 15N-labelled 1-azido-4-nitrobenzene. The
reaction proceeded with retention of 15N directly attached to
the aromatic ring (see Scheme S2, ESI†).
The role of the thiazolium salt 2 is uncertain and warrants
further investigation. However, preliminary mechanistic studies
with the thiazolium derived triazene 712,20 demonstrated that
such species are stable to the amidation conditions (Scheme 2).
Based upon the available experimental data, we present a 12 J. Burnley, G. Carbone and J. E. Moses, Synlett, 2013, DOI: 10.1055/
s-0032-1318216.
working mechanistic hypothesis. Thus, electron transfer from
the tert-butoxide ion gives the dianion 8, a process that we
13 H. Inoue and K. Higashiura, J. Chem. Soc., Chem. Commun., 1980,
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tentatively propose is catalysed by a thiazolium anion relay 14 During the preparation of this manuscript, Manetsch et al., reported
derived from 2 (13).12 Whereas protonation and loss of nitrogen
a novel, complementary tert-butoxide ion mediated amidation of
aldehydes with benzylic azides: S. S. Kulkarni, X. Hu and
R. Manetsch, Chem. Commun., 2013, 49, 1193–1195.
from 8 would deliver the corresponding aniline (Scheme 1),
¨
interception of the intermediate 8 by an aldehyde would deliver 15 S. Brase and K. Banert, Organic Azides: Syntheses and Applications,
intermediate 9.14 A subsequent 1,4-hydride shift leads to inter-
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16 K. Barral, A. D. Moorhouse and J. E. Moses, Org. Lett., 2007, 9,
mediate 10 that is poised to extrude nitrogen gas and deliver the
1809–1811.
dianion 11. Next, in a manner consistent with the observations 17 (a) R. D. Guthrie and D. L. Nutter, Bull. Soc. Chim. Belg., 1982,
of Guthrie,17 we speculate that the loss of two electrons from 11
91, 455; (b) R. D. Guthrie and D. L. Nutter, J. Am. Chem. Soc., 1982,
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occurs via SET, with concomitant formation of two equivalents
18 A. Russel, E. G. Jenzen and E. T Strom, J. Am. Chem. Soc., 1964, 86,
of the tert-butoxide anion from di-tert-butylperoxide. Overall
imidate 12, tert-butanol and tert-butoxide are generated which,
upon protic work-up delivers the corresponding amide 6 and
tert-butanol (Scheme 3).
1807–1814.
19 C. Tang and N. Jiao, J. Am. Chem. Soc., 2012, 134, 18924–18927.
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Chem. Commun., 2013, 49, 2759--2761 2761