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basic condition to furnish amine I and formaldehyde. We reported
here that with the aid of a carefully chosen (vide infra) base, this
design concept was found to indeed correspond to experimental
reality, thereby providing a new and efficient methodology for the
preparations of a series of structurally variable formamide-type
substances.
2. Results and discussion
With the uses of 5 mol % of Ru(bpy)3Cl2 photo-catalyst (in the
commercially available hexahydrate form), 45 W household light-
ing bulb, 5.0 equiv of externally added water and an O2 balloon
atmosphere, our initial reaction conditions screenings performed
on a standard vicinal diamine substrate 1 in MeCN solvent (60 h
stirring at room temperature) quickly uncovered a remarkable base
effect. As summarized in Table 1, the NMR internally calibrated-
yield of the desired product 2 was found to be sensitively de-
pendent on the nature of the base employed. Organic tertiary
amine-type base DBU9 of 3.0 equiv was shown to be a poor choice,
but the reaction with NaOH (3.0 equiv) demonstrated a significant
improvement (47% yield of 2). A few other inorganic bases were
thus examined and the results were as following: KOH (16%), K2CO3
(49%), Cs2CO3 (81%). Clearly, Cs2CO3 emerged as the superior ad-
ditive. When Cs2CO3 was used at reduced loading of 1.0 equiv, the
product yield was further enhanced to be nearly quantitative (97%),
while fewer amounts (0.5 equiv) were found to incur a significant
yield decrease to 69%. It is important to note that this optimized
protocol is readily amendable for scaling up without compromising
the efficiency, and the transformation of 1e2 was conducted at
gram-scale and the yield of isolated material was 90%. It also merits
commenting that in complete accord with our design concept,
when a less volatile vicinal diamine 1,2-bis(4-phenylpiperidin-1-yl)
ethane (i.e., the substrate 3h shown below in Scheme 2) was
employed in place of 1, both of the product 4h and the amine 4-
phenylpiperidine corresponding to the iminium ion pathway
product I were obtained in w1/1 molar ratio and in 90% combined
yield.
Scheme 2. Survey of reaction scope.
electronic densities of oxygen and nitrogen-atoms in the substrates
do not seem to interfere with their photo-oxidation events.
g-
Phenyl-substituted piperidine amide 4h was obtained in 90% yield.
Furthermore, purely acyclic vicinal diamines, either symmetrically
(3ie3m) or unsymmetrically substituted (3n), were all shown to be
competent substrates, and their corresponding formamides 4ie4n
were uneventfully isolated in moderate-to-high yields (45e82%).
The above-described ‘standard’ protocol was found to never-
theless be non-suitable for strained cyclic or aryl-substituted 1,2-
vicinal diamines. Presented in Scheme 3 are preliminary not the
anticipated formamide, but a new amide 6 in 75% yield bearing an
intact skeleton! The formation of 6 may best be rationalized by
base-promoted auto-oxidation11 of the in situ formed N,O-hemi-
acetal species. For aryl-substituted diamine 7, only trace amount of
formamide product 8 was detectable, suggesting the inefficiency of
an aryl-stabilized amine radical cation (i.e., species B) towards
further electronic fragmentation. Expanding the current method-
ology’s arena to these substrate types must therefore await further
experimental investigations.
Table 1
The base effect in formamide formation
Base
DBU
NaOH
KOH
K2CO3
CS2Cs2CO3
Cs2CO3
Cs2CO3
n (equiv)
3.0
Trace
3.0
47%
3.0
16%
3.0
49%
3.0
81%
1.0
97%
0.5
6.9%
Yielda
Gram-scale preparation of 2 accomplished at 90% isolated yield.
a
Yields were determined by 1H NMR using naphthalene as an internal standard.
A list of 1,2-diamine substrates generally structured as 3 were
next subjected to the above identified optimal reaction conditions,
and the results, as compiled in Scheme 2, evidently demonstrated
a considerably general scope.10 Piperidine-derived amide products
4ae4b bearing
isolated yields (90% and 92%, respectively), and their
g
- or
b
-methyl group were produced in similar
-methylated
Scheme 3. Notable experimental observations.
a
analog 4c, presumably due to the interference of steric hindrance,
was furnished in a much lower yield (66%). The unfavorable size
influence escalated further with the extreme bulky 3d, in which the
production of 4d was practically inhibited. A release of such steric
3. Conclusion
congestion simply by relocating the two
a
-dimethyl substitutions
In summary, we disclosed herein a remarkably simple and mild
protocol for converting a range of structurally variable 1,2-vicinal
diamines to the N,N-dialkyl substituted formamides. The apparent
values of this discovery leverage on three complementary facts that
there are currently rather limited methods known for preparations
of formamides that the starting materials employed herein are
to neighboring -positions in 4d immediately resumed the re-
b
activity, leading to product 4e in 80% yield. Morpholine and
piperazine-derived structures were well accommodated, and their
products 4f and 4g were furnished in 93% and 83% yields, re-
spectively. These results were notable in that the lone pair