A straightforward and versatile protocol for the direct conversion of benzylic azides to ketones and aldehydes

Article abstract of DOI:10.1039/c6ra13088g

The synthesis of carbonyl compounds from benzylic azides through benzylideneamides is described for the first time. NaH-mediated activation of benzyl azides allows a rapid water-promoted oxidation under a facile protocol with good yields.

Full text of DOI:10.1039/c6ra13088g

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A Straightforward and Versatile Protocol for the Direct Conversion
of Benzylic Azides to Ketones and Aldehydes
Davir González-Calderón,*a Marco A. Morales-Reza, Eduardo Díaz-Torres, Aydeé Fuentes-Benítes,
and Carlos González-Romero*a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
Previous works:
The synthesis of carbonyl compounds from benzylic azides
through benzylideneamides is described for the first time. NaH-
N3
O
reaction condition
a
e
mediated activation of benzyl azides allows
a rapid water-
Ar
Ar
Aldehydes
promoted oxidation under a facile protocol with good yields.
The chemistry of organic azides is very well-known. Books1 and
reviews2 have compiled the role of these valuable nitrogen
compounds as mediators between chemistry, medicine, biology and
materials science. As synthetic intermediates, organic azides can be
coupled to other substrates (e.g. 1,3-dipolar cycloaddition)3 or
directly converted to other functional groups, such by reduction
(e.g. Staudinger reaction)4 or by an oxidation process. Regarding the
latter, there are reports on obtaining nitro compounds5 (oxidation
of the –N3 moiety) as well as synthesizing nitriles6 (oxidation of
benzylic carbon). In this context, synthetic strategies to achieve
carbonyls from azido groups (Scheme 1)7 (an inverse reaction as
proposed by Ghorai) 8 are still challenging and attractive for organic
chemists. Unfortunately, all such strategies developed to date [Eq.
(a)–(f)] suffer from serious drawbacks, including the use of metals
as reagents that are very expensive and/or unconventional and
require the use of peroxides, as well as cumbersome experimental
procedures or high temperatures that are particularly
disadvantageous for large-scale reactions.
a
b
Prabhu (2008):
Severin (2011):
Zhang (2011):
Díez (2013):
MoO2(S2CNEt2)2 cat.
toluene, O2, reflux
ref. 7a
ref. 7b
ref. 7c
ref. 7d
[Cp^RuCl2]2 cat.
MeCN/H2O, reflux
c
d
FeCl3 cat.
CH2Cl2, H2O2, reflux
[Pd] cat.
Ph
Ph
MeCN/H2O, reflux
e
Fasan (2016):
Mb(H64V,V68A) cat.
(Fe as active metal)
Na2S2O4, KPi (pH 7.0),
MeOH/H2O, r.t.
ref. 7e
Metals
Scope only for primary
benzyl azides
ref. 7f
N3
O
V2O5 cat,
H2O,
f
Prabhu (2011):
Ar
R
tBuOOH exc.
reflux
Ar
R
Ketones
Metals
Strong oxidant
conditions
Scope only for
secundary
benzyl azides
Synthetic strategies involving the acidic hydrolysis of enamines
[Scheme 2, Eq. (g)] or imines [Eq. (h)] generated in situ from azide
compounds have been reported in literature. Hendrickson (1977)9a
and Hassner (1979)9b published the direct conversion of vinyl azides
to carbonyls via enamines in good yields. Although the thermal,
photolytic and acidic decomposition of organic azides to imines has
been studied extensively10,12g their applications for obtaining
carbonylic compounds11 are rather limited. The high temperatures
(ca. 300°C) required for a thermal process in the synthesis of alde–
This work:
1) NaH,
DMSO,
room temp.
N3
O
Ar
R
Ar
R
2)
H2O
Aldehydes or
Ketones
For primary and secundary
benzyl azides
No metals
Scheme 1. Recent advances in the synthesis of carbonyl derivatives from azide
compounds.
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Table 1. Optimization of reaction conditions:[a] Effect of solvent and base.
Previous works:
N3
O
N3
[P] or [S]
reagents
Base,
Solvent,
4 h
O
ref. 8
N
H3O+
1)
2)
R2
g
R2
R2
R1
R1
R1
H2O
(work-up)
Ketones
good yields
N2
enamine
1a
4a
Entry
1
Solvent
Base[b]
NaH
Yield (%)[c]
70
+
several
by-products
Thermal,
Photolytic or
Acidic process
ref. 10, 11 N3
O
NH
DMF anh.
DMF anh.
DMF anh.
DMF anh.
DMF anh.
DMF anh.
MeCN anh.
DMSO anh.
DMSO anh.
DMSO anh.
DMSO anh.
h
H3O+
2
K2CO3
NR[e]
NR[e]
60
R1
R2
R2
R1
R2
R1
3[d]
K2CO3
Aldehydes or Ketones
< 50% in most cases
imine
N2
4
tBuOK
5
KOH
Trace[e]
This work:
(no by-products)
O
N3
6[d]
KOH
45
N
Basic
conditions
H2O
fast
7
NaH
35
Ar
R
Ar
R
Ar
R
8
tBuOK
72
via imine
Aldehydes or
Ketones
good yields
N2
9
NaH
80
benzylideneamide
10
11
NaH (1.5 eq)
NaH (1.0 eq)
74[f]
70[f]
Scheme 2. Acidic hydrolysis of enamines (efficient) or imines (inefficient) generated in
situ from azide derivatives representing synthetic strategies for the attainment of
carbonyls.
[a] Unless otherwise stated, reactions were run at room temperature for 8 h.
[b] Unless otherwise stated, reactions were performed using 2.0 eq.
[c] Yields refer to chromatographically pure isolated compounds.
[d] These experiments were carried out at 60 ºC.
[e] Starting material was recovered.
hydes from alkylic azides12a (inefficient for benzylic azides)12b
preclude the use of this type of reaction for most substrates. In
contrast, a photolytic process using primary alkyl azides12c–f occurs
at or below room temperature. However, its use is limited by very
low yields (18–50%) from a complex reaction mixture. Finally, trace
amounts of carbonyls have been observed under strong acid
conditions.[12g–i] The evident inefficiency of all these methods as
synthetic strategies to afford carbonyls from azides via imines has
led to complete disinterest and abandonment of their use, a fact
that has been demonstrated by the absence of studies in
contemporary literature. [13]
Previously Manetsch[14a] and Wu/Pan[14b] demonstrated the
tBuOK-promoted attainment of PhCH=N– (benzylideneamide) from
PhCH2N3 as well as its inefficient use for coupling the latter with
carbonyl compounds. We herein describe the utility of
benzylideneamides for directly converting benzyl azides to carbonyl
derivatives with good yields.
[f] Along with the corresponding starting material (~15% recovered)
1) NaH (2.0 eq),
DMSO anh.,
4 h, r.t., N2
N3
O
4
R
H
O
R
2) H2O
1
O
O
Cl
MeO
O
H
H
H
O
MeO
MeS
OMe
OMe
4c, 76%
4d
, 71%
O
4b
, 74%
O
O
H
H
H
(H3C)2N
4g, 80%
4e
, 75%
4f
, 84%
During one of our current research programs, focused on the
development of novel methodologies for the construction of 1,2,3-
O
H
O
O
H
triazole
moieties
through
base-promoted
azide-ketone
S
H
cycloadditions[15] we observed that when NaH was subjected to our
study, benzaldehyde was isolated as by-product along with the
corresponding triazole. Intrigued by this outcome, we decided to do
follow-up investigation this fact in greater detail.
O
4j
, 87%
Cl
4i, 72%
4h, 78%
O
O
Cl
O2N
H
H
H
Firstly, in absence of ketones (in order to avoid the formation of
the corresponding triazole) good yields were observed at room
temperature with a reaction time of 4 h. Secondly, the effects of
solvents and bases on compound 1a were observed in optimization
studies (Table 1). The best performance was found for NaH (entry
9) in dimethyl sulfoxide using 2.0 equivalents of the base. The
optimized conditions were then used to study the direct conversion
of a variety of azides† to aldehydes (Scheme 3).‡ In order to
evaluate the scope of our protocol, both benzylic and aliphatic
azides were subjected to the optimized reaction conditions.
Unfortunately, aliphatic compounds (4n and 4o) did not react to
Cl
O2N
(not obtained)[a]
4k, 18%[a]
(not obtained)[a]
4l
4m
O
H
[a] Complex reaction mixture
[b] Starting material recovered
Ph
Ph
H
O
(no products)[b]
(no products)[b]
4n
4o
Scheme 3. Direct conversion of primary azides (1) to aldehydes (4) under optimized
conditions. Reaction conditions: NaH (0.2 mmol) was added to a solution of compound
1 (0.1 mmol) in DMSO anh. Then, water was added in excess.
2 | J. Name., 2012, 00, 1-3
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According to these results, a plausible mechanism is proposed
in Scheme 5. The generation of benzylideneamide (III) by a base-
promoted deprotonation of the benzyl azide (I) is supported by
previous studies (Manetsch[14a] and Wu/Pan[14b]). We propose that
this was followed by a rapid hydrolysis under basic conditions
leading to the corresponding carbonyl group (VI).
1) NaH (2.0 eq),
DMSO anh.,
4 h, r.t., N2
N3
O
6
Ar
R
Ar
R
2) H2O
5
O
O
O
NC
CH3
MeO
6c
, 83%
[a]
6a
, 85% (80%)
6b
, 78%
O
N
O
O
N3
N3
N
N
B
CH3
N
CH3
Ar
R
Ar
R
PhH2CO
6f
Ar
R
N2
H3C
6d, 83%
Cl
(I)
Ar
R
(III)
OCH2Ph
O
(II)
6e, 83%
, 77%
H2O
Br
O
O
6g, 81%
CH3
O
S
N
H
N
O
CH3
NH3
O
H
NH2
N
H
H
6h, 77%
O
R
Ar
R
Ar
HO
R
Ar
(V)
O
(VI)
N
(IV)
O
O
6i
, 75%
CH3
Scheme 5. Proposed plausible mechanism for direct conversion of benzyl azido groups
(no products)[b]
6j
, 73%
6k
to carbonyl derivatives.
O
O
CH3
CH3
Conclusions
F
O2N
[c]
(not obtained)[c]
(not obtained)
In summary, we report that the benzyl azido group is directly
converted to carbonyls in good yields through a rapid hydrolysis
6m
6l
[a] from 10.0 g of starting material
[b] Starting material recovered
[c] Complex reaction mixture
(basic
conditions)
of
benzylideneamides
generated
readily/efficiently in situ. We are convinced that this synthesis is the
most versatile reported so far as its scope includes both primary
azides (affording aldehydes) and secondary azides (affording
ketones) reacted with conventional reagents under a very simple
procedure.
Scheme 4. Direct conversion of secondary azides (5) to ketones (6) under optimized
condicions. Reaction conditions: NaH (0.2 mmol) was added to a solution of compound
5 (0.1 mmol) in DMSO anh. Then, water was added in excess.
such conditions remaining intact in the flask even under thermal
conditions (60 ºC). Therefore, only benzylic azides were considered
for the present study. An effective approach to the aldehyde
derivatives was carried out with heterocycles (4j), strongly (4c, 4d,
4e, 4g and 4i) and weakly (4f) activated rings as well as weakly
deactivated (4h) rings. The exception was strongly deactivated rings
(4k, 4l and 4m).
Acknowledgments
We gratefully acknowledge financial support from the
Secretaría de Investigación
y Estudios Avanzados-Universidad
Autónoma del Estado de México (grant No.3804/2014/CID) and
CONACYT-Mexico (postgraduate scholarship No. 227581). The
authors would like to thank the referee for valuable comments and
suggestions, and M.N. Zavala-Segovia and L. Triana-Cruz (CCIQS
UAEM‒UNAM) for technical support.
Encouraged by these outcomes, we decided to investigate
another possibility: the synthesis of ketones using secondary azido
groups. We therefore submitted the (1-azidoethyl)benzene
[PhCH(N3)CH3] to the current protocol achieving the synthesis of the
corresponding acetophenone (6a, Scheme 4) with good yields
(85%). Therefore, a series of compounds containing secondary
azides† were studied under the same reaction conditions.‡
At this stage we found the behavior similar to that observed for
primary azides including the lack of reaction for aliphatic (6k) and
strongly deactivated aromatic rings (6m). Two interesting
exceptions were N≡C– [a strongly deactivating derivative (6b)] and
F–substituted [a weakly deactivating derivative (6l)].
Notes and references
†
Azide compounds (starting materials) were obtained from the
corresponding alcohols[16], halides[17] or tosylates[18] according to
synthetic protocols described in literature.
‡ General experimental procedure for the direct conversion of
azides to carbonyls: NaH (0.4 mmol, 60 % dispersion in mineral oil)
was added to a solution of the azide derivative (0.2 mmol) in
anhydrous dimethyl sulfoxide (ca. 2.0 mL/mmol). The solution was
stirred at room temperature for 4 h under an inert atmosphere.
Brine (ca. 20.0 mL) was added to the reaction stirring vigorously for
15 min. Then, the mixture was washed with ethyl acetate (3 x 8 mL).
The organic layer was dried (Na2SO4), and the solvent was
evaporated under reduced pressure. The crude extract was purified
Finally, in order to demonstrate the scalability of such protocol,
acetophenone (6a) was efficiently obtained (80%) from 10.0 g of
the corresponding starting material [PhCH(N3)CH3]. The use of ice
bath was necessary due to the exothermic reaction observed along
with the intense bubbling (N2↑) during the addition (in five portions)
of the hydride.
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Chem. Rev. 1954
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Graphical and textual abstract for the contents pages
1) NaH (2.0 eq),
DMSO,
No metals
N3
O
No strong oxidants
Simple protocol
room temp.
Ar
R
Ar
R
H2O
2)
Conventional reagents
Wide substrate scope
R = H: Aldehydes
10 examples
>70%
R = Alkyl: Ketones
10 examples
We report that the benzyl azido group is directly converted to carbonyls in good yields
through rapid hydrolysis (basic conditions) of benzylideneamides generated
readily/efficiently in situ under a very simple procedure involving conventional reagents.
a