Dieter Enders et al.
For instance, a homo-benzoin reaction could take place,
which is known to favor electron-deficient substrates be-
cause of the formation of a more-stable Breslow intermedi-
ate.[3] Pleasingly, on changing from aromatic to aliphatic al-
dehydes for the aza-type benzoin reaction, we found that
enolizable substrates, such as alkyl-substituted aldehydes,
were also reactive, thereby generating products 4p, 4q, and
4r in 83%, 78%, and 84% yield, respectively. However, the
necessary reaction time increased in these cases. Finally, the
reaction with 3-methoxybenzaldehyde was performed in an
excellent 92% yield (4s). 2-Chlorobenzaldehyde was also
studied, but, disappointingly, no product was obtained.
The second part of our investigation into the substrate
scope of this reaction focused on the variation of the enal
component (3) in the subsequent redox esterification step.
Interestingly, the observed reactivity was in line with the ob-
servations for the preliminary aza-benzoin-type reaction.
In comparison, an aldehyde with an electron-rich 4-tolyl
group generated the final product (4) in similar yields as un-
substituted cinnamaldehyde 3a (Table 2, entries 4a/4e, 4b/
4 f, and 4c/4g). However, the reaction time that was needed
to complete the reaction was significantly longer. On the
other hand, electron-deficient enals, such as 4-chloro- or 4-
nitro-cinnamaldehyde, showed lower yields and shorter re-
action times (Table 2, 4h–4m). For the aza-benzoin-type re-
action, a possible explanation of this result is an electroni-
cally controlled side reaction, such as the homo-benzoin re-
action. To expand the scope of this reaction to include ali-
phatic enals, we also tested crotonaldehyde as a substrate. In
this case, to our delight, compound 4t was obtained in 81%
yield. In addition, steric effects were also studied by using
ortho-methoxycinnamaldehyde and compound 4u was ob-
tained in 75% yield.
Scheme 3. Proposed pathway for the NHC-catalyzed one-pot reactions.
same catalyst (A’) and, hence, involve structurally analogous
Breslow intermediates (IN1 and IN3). The comparable elec-
tronic properties of these intermediates are responsible for
the observed trends with the various substrates, as men-
tioned above.
In summary, we have developed a new NHC-catalyzed
one-pot reaction between nitrosobenzenes 1, aldehydes 2,
and enals 3 to afford hydroxamic esters 4 in a one-pot, two-
step reaction. Initially, an aza-benzoin-type condensation re-
action between nitrosobenzenes 1 and aldehydes 2 catalyzed
by an NHC took place. Subsequently, the resulting N-arylhy-
droxamic acids (5) reacted with enals 3 through an NHC-
catalyzed redox esterification reaction in the same pot with-
out the addition of any other reagents. This two-step, one-
pot sequence afforded the desired hydroxamic esters (4) in
good yields and tolerated a broad range of aliphatic and ar-
omatic substrates. This class of compounds is known to ex-
hibit potential anti-inflammatory and anti-cancer activities.
In the final part of our investigation, we examined the
scope of nitrosobenzenes 1 in this reaction. Therefore, nitro-
sobenzene (1a), electron-rich 4-methylnitrosobenzene, and
electron-deficient 3-nitronitrosobenzene were subjected to
the optimized reaction conditions. In three comparable ex-
periments, the corresponding products 4a, 4n, and 4o were
obtained in 87%, 57%, and 69% yield, respectively. This
result indicates that unsubstituted nitrosobenzene 1a was
much better than substituted nitrosobenzenes, no matter
whether electron-rich or electron-deficient groups were
present.
Lastly, a domino reaction was envisaged that utilized both
reaction steps with cinnamaldehyde 3a as the sole aldehyde
component aside from nitrosobenzene 1a. Indeed, the de-
sired domino product (4v) was formed in very good yield
(80%) after a short reaction time of 30 min. A similar reac-
tion was reported by Ying and co-workers in 2008.[5]
The proposed pathway for the NHC-catalyzed one-pot re-
action is shown in Scheme 3. Firstly, an aza-benzoin-type re-
action between nitrosobenzene 1 and aldehyde 2 forms the
Experimental Section
General Procedure for the Synthesis of the Hydroxamic Esters
TMEDA (0.1 mmol) was added under an argon atmosphere to a solution
of nitroso compound 1 (0.5 mmol), aldehyde 2 (0.5 mmol), and triazolium
salt A (0.05 mmol) in CH2Cl2 (5 mL) and the mixture was stirred at RT
for 15–40 min. Then, enal 3 (1.0 mmol) was added under an argon atmos-
phere to the resulting mixture, which was stirred for an additional
20 min–3.5 h. The product was isolated by short column chromatography
on a silica gel.
À
C N bond in N-arylhydroxamic acid 5. Secondly, the subse-
quent addition of enal 3 initiates the redox esterification of
N-arylhydroxamic acid 5 to afford the corresponding satu-
rated ester (4). In this context, both cycles operate with the
3
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Chem. Asian J. 2013, 00, 0 – 0
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