A simple base-mediated amidation of aldehydes with azides

Article abstract of DOI:10.1039/c2cc37289d

A practical and efficient amidation reaction involving aromatic aldehydes and various azides under mild conditions is described. A broad spectrum of functional groups was tolerated, and the amides were synthesized in moderate to excellent yields, presenting an attractive alternative to the currently available synthetic methods.

Full text of DOI:10.1039/c2cc37289d

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A simple base-mediated amidation of aldehydes with
azides†
Cite this: DOI: 10.1039/c2cc37289d
Sameer S. Kulkarni, Xiangdong Hu and Roman Manetsch*
Received 6th October 2012,
Accepted 23rd November 2012
DOI: 10.1039/c2cc37289d
www.rsc.org/chemcomm
A practical and efficient amidation reaction involving aromatic amides in moderate yields. Strikingly, this reaction failed to afford
aldehydes and various azides under mild conditions is described. the desired amide when benzyl or n-butyl azide was used. The
A broad spectrum of functional groups was tolerated, and the reaction of benzyl azide is of particular interest since it leads to
amides were synthesized in moderate to excellent yields, presenting amidomethylarenes. In fact, a variety of therapeutic agents such as
an attractive alternative to the currently available synthetic methods. Picotamide,20 Raltegravir21 and others22 are comprised of an amido-
methylarene moiety. Recently, Molander et al. reported a synthetic
The amide bond serves as one of the nature’s most fundamental route to generate these types of molecules via a C–C bond forming
functional groups. Indeed, it is an integral component of a large reaction between amidomethyltrifluoroborates and aryl or heteroaryl
number of organic and biological molecules such as pharmaceuticals, chlorides.22c Although a wide range of substrates were tolerated
natural products, peptides, and proteins. Traditionally, the amide under the reported reaction conditions, a tedious 4-step sequence to
functionality is incorporated through a reaction of an amine with access amidomethyltrifluoroborates demanding long reaction times,
either an activated carboxylic acid (generally acid halides or high temperatures and the Pd catalyst required in the following C–C
anhydrides) or by an activation using carbodiimide coupling reagents. bond formation are the drawbacks associated with this approach.
However, several innovative approaches have been developed in the Therefore, a simple, convenient method deprived of the aforemen-
past decade, which include the Staudinger reaction,1 the a-bromo tioned disadvantages would be of great interest. We herein unveil
nitroalkane–amine coupling,2 the native chemical ligation,3 the thio a straightforward protocol starting from azides and aromatic
acid–azide amidation,4 the alkyne–sulfonyl azide coupling,5 the aldehydes to synthesize amidomethylarenes under mild basic
coupling of acyltrifluoroborates with hydroxylamines6 or azides,7 the conditions (Scheme 1).
Au/DNA-catalyzed amidation from alcohols and amines,8 the amino-
Initially, the reaction conditions were screened using benzyl
carbonylation of aryl halides,9 and the Pd catalyzed coupling of aryl azide and benzaldehyde as the model substrates. The summary of
halides with isocyanides.10 Additionally, numerous one-pot oxidative these results is presented in Table 1. Surprisingly, among the non-
amidation methods have been reported wherein, aldehydes,11 nucleophilic bases tested, t-BuOK alone produced the desired amide
alcohols12 or alkynes13 are oxidized using transition metal catalysts (see the ESI†). From the set of the solvents explored, polar aprotic
and treated with amines yielding corresponding amides. Meanwhile, solvents such as THF, DMF, and DMSO proved to be suitable for this
some environmentally benign metal-free amidation procedures transformation, DMF offering the best results. In the course of
employing silyl reagents14 or oxidants like sodium chlorite,15 further optimization, increasing the amount of t-BuOK to 2 eq. was
peroxide16 have also been exploited.
found to significantly improve the yield of the product. Furthermore,
Another important approach to amides is the Schmidt reaction,17 the reaction was completed in 15 min at room temperature making
involving ketones and hydrazoic acid. Aube and co-workers have it a highly efficient and practical synthetic route. Having the reaction
reported an intramolecular Schmidt reaction of cyclic ketones to conditions optimized, the scope of the reaction involving benzyl
construct N-substituted lactams in which hydrazoic acid was azide and a diverse array of aldehydes was first examined (Table 2).
replaced by an alkyl azide.18 An interesting extension of this reaction, Aromatic aldehydes bearing electron-donating groups afforded
known as the Boyer reaction,19 was first reported19a in 1950s, excellent yields although an excess amount of the base was required
wherein, two aromatic aldehydes were reacted with b-phenylethyl
azide under harsh acidic conditions generating the corresponding
Department of Chemistry, University of South Florida, 4202 E Fowler Ave., Tampa,
FL – 33620, USA. E-mail: manetsch@usf.edu; Tel: +1 8139747306
† Electronic supplementary information (ESI) available: Experimental section and
Scheme 1 Reaction between azides and aromatic aldehydes yielding amides.
the spectral data of all new compounds. See DOI: 10.1039/c2cc37289d
c
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Table 1 Optimization of the reaction conditionsa
Table 3 Reaction of various azides with benzaldehydea,b
Entry
Base
Solvent
Yieldb (%)
1
2
3
4
5
6
7
DIPEA
Cs2CO3
DBU
t-BuOK
t-BuOK
t-BuOK
t-BuOKc
DMF
DMF
DMF
DMF
THF
DMSO
DMF
—
—
—
50
40
23
72
a
General reaction conditions: 1a (0.5 mmol), 2a (0.6 mmol), base
b
a
(0.75 mmol), solvent (2.5 mL), 15 min. Isolated yields based on
1a. t-BuOK (1.0 mmol).
Reaction conditions: 1 (0.5 mmol), 2a (0.6 mmol), t-BuOK (1.0 mmol),
c
b
DMF (2.5 mL), 15 min. Isolated yields based on 1.
in some cases (3ad, 3aj, and 3al). Changing the position of methoxy
substituent on the aromatic ring from para to meta did not affect the
yield (3ab and 3ac). However, the amidation reaction with the
sterically challenging 2-methoxybenzaldehyde offered a moderate
amount of the product (3ad). Substrates such as 3-methylbenzalde-
hyde, 4-(methylthio)benzaldehyde, [1,10-biphenyl]-4-carbaldehyde
and 1-naphthaldehyde led to the formation of desired products
3ae–3ah in good to excellent yields. Functional moieties like
1,3-dioxolane (3ai) and N,N-dimethylamine (3aj) were well tolerated
as well. Heterocyclic substrates such as furan and indole derivatives
provided excellent results (3ak and 3al). Among aldehydes with
electron-withdrawing substituents, 4-chlorobenzaldehyde exhibited
great compatibility (3am) whereas, lower yield was obtained when
4-cyanobenzaldehyde was used (3an). Cinnamaldehyde, despite
being a Michael acceptor, did undergo the reaction (3ao) albeit with
poor yield. Unfortunately, the aliphatic aldehydes are not appro-
priate starting materials under these reaction conditions due to the
presence of a more acidic a-proton.
heteroaryl moiety proceeded smoothly resulting in amide 3da.
Benzyl azides containing electron-donating substituents were found
to be suitable substrates for this reaction (3ea and 3fa). It is
noteworthy to mention that an azide with both electron-donating
and withdrawing functionalities furnished the amide 3ga in 77%
yield. Substrates with sterical hindrance participated well under
these reaction conditions (3ha and 3ia). In pursuit of substrates
other than the substituted benzyl azides, we discovered that the
a-azido amides also take part in this reaction efficiently providing
moderate yields for the corresponding diamides 3ja, 3ka, and 3la. An
acid labile Boc group was obviously unaffected (3ka) under these
conditions, offering an advantage over the Boyer reaction. Aromatic
and other aliphatic azides failed to generate corresponding amides
under the reaction conditions described herein. Nevertheless, innoc-
uous by-products (molecular nitrogen and t-BuOH), short reaction
time, ambient temperature and easily accessible starting materials
make it an attractive alternative to the contemporary synthetic routes.
Intrigued by the outcome of this study, we decided to delve into
the mechanistic details of this reaction. A control experiment was
designed wherein t-BuOK was added to a solution of azide 1a in DMF
resulting in a deprotonation followed by the loss of molecular nitrogen
leading to benzylideneamide 5 (Scheme 2A). After 10 minutes of
stirring, aldehyde 2a was added to the reaction mixture. Interestingly,
the desired amide 3aa was formed only in trace amounts. On the
contrary, when a mixture of azide 1a and aldehyde 2a in DMF was
treated with t-BuOK, amide 3aa was obtained in 72% yield (Table 2).
This implies that the intermediate benzylideneamide 5 loses its
reactivity towards aldehyde, failing to generate an amide. Whereas, if
the reactive species 4 formed by addition of t-BuOK reacts with the
aldehyde prior to the elimination of molecular nitrogen, an amide is
obtained suggesting that, the nucleophilic attack of outermost
nitrogen atom in species 4 on the carbonyl carbon of aldehyde is
crucial for the reaction to proceed. It is worth mentioning that, the
azides are generally electrophilic under basic conditions.
These encouraging results prompted us to expand the scope of
this reaction with respect to the azides (Table 3). Benzyl azides
consisting of electron-withdrawing substituents were successfully
converted to the amides 3ba, 3ca, and 3da in moderate to substantial
yields. Especially, the reaction of an azide incorporated on a
Table 2 Reaction of benzyl azide with various aromatic aldehydesa,b
Based on these results, a plausible mechanism is proposed
(Scheme 3). The first step would involve a deprotonation of
benzyl azide, generating a highly reactive species 4. Resonance
structure 4-B can readily react with the benzaldehyde 2a leading
to an intermediate 6 followed by a 1,5-hydride shift resulting in
triazenide 7. An intramolecular nucleophilic attack on the
carbonyl carbon would produce 8, which would be converted
a
Reaction conditions: 1a (0.5 mmol), 2 (0.6 mmol), t-BuOK (1.0 mmol),
b
c
DMF (2.5 mL), 15 min. Isolated yields based on 1a. t-BuOK (2.0 mmol).
c
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Notes and references
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To support our hypothesis, another experiment was conducted
wherein the benzaldehyde was replaced by benzaldehyde-a-d1
(Scheme 2B). If the reaction follows the mechanism proposed above,
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Scheme 3 Plausible reaction mechanism of amidation.
c
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