Angewandte
Communications
Chemie
with either strongly electron-withdrawing (CF3, 3h; 3,4-
dichloro, 3l) or strongly electron-donating groups (dioxo,
3m) provided comparable yields. Hydrazones prepared from
benzaldehydes with phenyl, benzyloxy, or naphthyl substitu-
ents were poorly soluble in THF (1’j, 1’k, 1’n, and 1’o). In
these cases, the corresponding hydrazones were separated by
a simple filtration because of their facile precipitation. As
a result, the direct use of these solid hydrazones (1’) afforded
moderate yields of the corresponding amines (3j, 3k, 3n, and
3o). In cases where low yields were obtained, most of the
imine substrate 2a was recovered (3d, 3g, and 3n). The
couplings of heteroaromatic aldehydes, such as 2-furan-,
3-pyridine-, and 3-thiophenecarboxaldehyde, proceeded well
to give the corresponding products in good yields (3p–3r).
Finally, aliphatic aldehydes were also effective in this reaction
but the desired products were formed in lower yields owing to
competing elimination reactions (3s–3u).
Having established the scope of the reaction with respect
to the nucleophilic partner, we moved on to investigate the
suitability of various electrophilic imines (Scheme 4). A wide
range of substituted aromatic imines were coupled with para-
chlorobenzylidene hydrazine (1’a) or benzylidene hydrazine
(1’b) in moderate to good yields. We identified a mild
electronic influence on the reactivity upon varying the
aromatic substituent on the imine carbon atom. For example,
the yield dropped from 82% to 56% when an electron-
withdrawing fluoro substituent was replaced with an electron-
donating 1,3-dioxole substituent (4c and 4 f). This result may
be explained in terms of the decreased electrophilicity of the
corresponding imine. By contrast, a dramatic electronic
influence was observed for variations of the aromatic
substituent on the imine nitrogen atom. Compared with 4d,
4i, which features a para-methyl instead of a hydrogen
substituent, was formed in significantly lower yield. With
N-piperonylidene (para-tolyl)amine (2j), a very electron-rich
imine, the yield even dropped to only 10%. To our delight,
upon modifying the reaction conditions by adding hydrazone
1’a in five portions (with a 30 minute interval), the yield was
improved to 44% (4j). The yields also improved when
a chlorine substituent, as a weakly electron-withdrawing
group, was attached to the aromatic ring on the imine
nitrogen atom (4k–4m). We also found that the coupling of
an imine with a naphthalene-1-yl group at the nitrogen atom
(4n, 60%) is slightly more efficient than that of the
corresponding imine with the naphthalene-1-yl group at the
imine carbon atom (4h, 47%). These results confirmed that
the steric influence of substituents on the imine carbon atom
is stronger than that resulting from substituents on the
nitrogen atom. Notably, sensitive functional groups that are
incompatible with robust organometallic reagents, such as
esters, amides, and nitriles, remained untouched in this
process. Similarly, the poor reactivity of 4p is likely due to
the electron-donating nature of the acetamido group.
Scheme 4. Imine scope. Yields of isolated products are given. Reac-
tions conditions: 2a (0.2 mmol), 1a or 1b (0.3 mmol, 1.5 equiv).
[a] The hydrazone was added in five portions with 30 min intervals
(2.5 h in total). [b] The gram-scale reaction was performed using 2t
(4 mmol) and 1a (6 mmol) in the presence of [Ru(p-cymene)Cl2]2
(0.75 mol%) and dmpe (1.5 mol%).
2u) were examined in the current process, and all afforded the
corresponding products in good yields (Scheme 4, 4s–4u).
Unfortunately, aliphatic imines such as N-propylidene aniline,
N-benzylidene methanamine, and N-benzylidene benzyla-
mine, as well as ketimines such as N,1-diphenylethan-1-imine
were comparatively inert under the standard conditions.
Finally, this method was assessed on a larger scale.
Gratifyingly, 1.03 g of 4t were obtained from 0.92 g of imine
2t (4 mmol) at 608C, with only 0.75 mol% of Ru(p-cyme-
ne)Cl2]2 and 1.5 mol% of dmpe, which corresponds to a yield
of 72% (Scheme 4, 4t). To facilitate this scale-up manipu-
lation, a three-neck round-bottom flask with a condenser
equipped with a nitrogen balloon was used as an alternative
reaction vessel.
In summary, we have developed a method for the
umpolung addition of aldehydes to aryl imines that is
mediated by hydrazine in the presence of a ruthenium(II)
precatalyst and dmpe. This process features aldehyde-derived
alkyl carbanion equivalents, complementary to the oxygen-
ated carbanions used in traditional coupling reactions
between carbonyl compounds and aryl imines. Compared to
classical organometallic coupling reactions, this approach not
Dibenzoxazepines, seven-membered aza heterocycles
featuring cis imines, are commonly found in a large number
of bioactive molecules. Many of them display interesting
physiological activities and can be used as antidepressants,
antipsychotics, and HIV-1 reverse transcriptase inhibi-
tors.[12,13] Three dibenzo[b,f][1,4]oxazepine derivatives (2s–
Angew. Chem. Int. Ed. 2016, 55, 1 – 5
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