Angewandte
Chemie
DOI: 10.1002/anie.201200313
Synthetic Methods
Reductive Azidation of Carbonyl Compounds via Tosylhydrazone
Intermediates Using Sodium Azide**
Josꢀ Barluenga,* Marꢁa Tomꢂs-Gamasa, and Carlos Valdꢀs*
The azide functionality has drawn considerable interest since
the late 19th century as a result of its versatile reactivity.
Organic azides have found wide application in organic
synthesis as precursors of fundamental nitrogen functional-
ities[1,2] as well as of nitrogen-containing heterocycles. More-
over, the development of the Cu-catalyzed azide–alkyne
cycloaddition,[3,4] the most representative example of click
chemistry,[5] has established new perspectives for the use of
Scheme 1. Metal-free reductive couplings between carbonyl com-
pounds and boronic acids (a), alcohols (b), and azides via tosylhydra-
zone intermediates.
azides in drug discovery[6] and also in materials science,
supramolecular chemistry, polymer chemistry, and biotech-
nology.[7] Thus, azides have recently acquired a privileged
position at the interface between chemistry, biology, medi-
cine, and materials science.
from 4-methylacetophenone 1a and sodium azide. The results
are briefly summarized as follows: 1) heating of tosylhydra-
zone and azide anions in the presence of base led to a complex
mixture constituted primarily of hydrazone degradation
products; 2) the formation of the expected benzyl azide 2a
requires the presence of tetrabutylammonium bromide
(TBAB) as the phase transfer catalyst; 3) other parameters,
for example, base (potassium carbonate), temperature
(1108C), solvent (1,4-dioxane), stoichiometric ratio (1a/
NaN3/base/TBAB = 1:3:1:3), were optimized (Table 1,
entry 1); thus, the treatment of N-tosylhydrazone 1a
(1 equiv, 0.1m) with sodium azide under the above reaction
conditions afforded the azide 2a in a reasonable 60% yield
after purification.
The common incorporation of the azide group into
organic frameworks relies on the classic nucleophilic sub-
stitution reaction of appropriate electrophilic substrates with
azide anions.[8] Other methods for the synthesis of alkyl azides
involve diazo transfer reactions to alkyl amines,[9] reactions of
carbon nucleophiles with electrophilic azides,[10] and hydro-
azidations of alkenes.[11] Importantly, while the reductive
amination of carbonyl compounds is recognized as one of the
most general protocols to synthesize amines, access to alkyl
azides from carbonyl compounds remains almost unknown. In
this context, Banert et al. have recently demonstrated the
generation of a-azidoalcohols by hydroazidation of aldehydes
with hydrazoic acid.[12]
On the other hand, tosylhydrazones are versatile tools for
With this protocol in hand, the scope of the reaction was
investigated, thus a series of representative hydrazones 1 was
subjected to the optimized reaction conditions. It must be
noted that the volume of solvent as well as temperature and
reaction times had to be optimized for each particular
substrate (Table 1). The reaction works well for both alde-
hydes (Table 1, entries 7–12) and ketones (entries 1–6, 13, and
14) furnishing primary and secondary alkyl azides, respec-
tively. Aromatic carbonyls with electron-withdrawing
(Table 1, entries 4–7) and -donating groups (entries 1–3, 8,
and 9) as well as with halogen substituents (entries 4 and 6)
are perfectly compatible with the reaction conditions. More-
over, heteroarylcarbonyl compounds, both p-excessive and p-
deficient heterocycles, afforded moderate yields of the
corresponding azides (Table 1, entries 10 and 11, respec-
tively). Interestingly, the azide functionality can be efficiently
installed in the a position of an ester, as is exemplified in
entry 13 in Table 1.
the modification of carbonyl compounds.[13] On the basis of
À
À
our previous work on metal-free C C and C O bond-forming
reductive coupling of tosylhydrazones (Scheme 1, a and b,
respectively),[14] we now report a new synthesis of alkyl azides
À
that is based on a new metal-free C N bond-forming
reductive coupling reaction (Scheme 1).[15,16] Specifically,
primary and secondary azides are prepared from carbonyl
compounds by reductive azidation of the readily available
tosylhydrazones as carbonyl surrogates with azide anions.
To establish the appropriate reaction conditions, some
experiments were undertaken with the hydrazone derived
[*] Prof. J. Barluenga, Dr. M. Tomꢀs-Gamasa, Dr. C. Valdꢁs
Instituto Universitario de Quꢂmica Organometꢀlica “Enrique
Moles”. Universidad de Oviedo
c/Juliꢀn Claverꢂa 8. Oviedo. 33006 (Spain)
E-mail: barluenga@uniovi.es
We then moved to the development of the one-pot version
of this transformation. With our previous background in this
field it was straightforward to establish a new protocol by
using carbonyl compounds as the starting materials
(Scheme 2). By heating these substrates in the presence of
tosylhydrazide at 808C for 90 min and subsequently adding
[**] Financial support of this work by DGI of Spain (CTQ2010-16790)
and Consejerꢂa de Educaciꢃn y Ciencia of Principado de Asturias
(IB08-088). A FPU predoctoral fellowship to M.T.-G. is gratefully
acknowledged.
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2012, 51, 1 – 4
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1
These are not the final page numbers!
Barluenga, Jose
