Organic Letters
Letter
isolation procedure by means of filtration; however, routinely
applied purification of the reaction mixture by flash chromatog-
raphy after evaporative workup led to higher yields in general.
Interestingly, the condensation reaction also works in water,
where 2 precipitates and could be isolated in 21% yield. With 2 in
hand, we proceeded in studying a qualitative stability profile in
DMSO (as the preferred solvent for storage and biological
screening) as well as at different pH values (pH 5, 7, 9 and water).
Although 2 was completely stable over 4 months in DMSO, the
compound decomposed within hours at pH 5 but showed
increased stability at higher pH values, being the most stable at
pH 9 (see the Supporting Information). This rather pronounced
susceptibility toward lower pH values was surprising, and in
retrospect, it might explain why compounds such as 2 did not
appear in the literature over the last few decades.
stability of these compounds toward neutral and slightly basic
conditions (pH 7, water, and 9) appeared to be increased.
Notably, 5 and 6 were stable under the routinely applied LCMS
conditions. These results clearly showed that it is in principle
possible to increase stability of the boratriazaroles in a wider pH
range.
It was interesting to notice that the condensation reaction (as
given in Table 2) between 1 and 2- or 4-pyridylboronic acid did
Table 2. Scope and Limitations
We confirmed the structure of 2 by single-crystal X-ray analysis
(Figure 1). The molecule is mostly flat, with torsion angles of
entry
R
solvent
product
yield (%)
a
1
Me
THF
3
47
56
47
26
52
56
62
50
58
55
0
b
2
2,6-F2C6H3
MeOH
MeOH
MeOH
4
c
3
2,6-Cl2C6H3
5
d
4
2,6-Me2C6H3
1-naphthyl
6
e
5
DMF
7
6
2,5-Me2-3-thienyl
2,4-Me2C6H3
(E)-CHCH-p-toluyl
2-(CF3)C6H4
2,6-(MeO)2-3-pyridyl
2-pyridyl
DMF
DMF
DMF
DMF
DMF
MeOH
MeOH
8
7
9
8
10
11
12
13
14
9
10
11
12
f
Figure 1. X-ray structure of boratriazarole 2 with thermal ellipsoids
shown at 50% probability level.
g
4-pyridyl
0
a
b
c
7 d at 95 °C. No reaction in MeOH at 95 °C. 95 °C for 2 h. 90 °C
d
e
2.0° and 15.6° between the central borotriazarole and the phenyl
and pyridine rings, respectively. A comparison of ring geometry
reveals the borotriazarole moiety to be an excellent isostere for
pyrazole and imidazole (Figure 2). A superposition with both
for 17 h. 95 °C for 1 d. Entries 5−10: the reaction was stirred for 3 h
at 100 °C. No product formation in MeOH (95 °C) or in pyridine
(90 °C). In MeOH at 95 °C, only the formation of bismethoxy ester
of the boronic acid was observed.
f
g
not proceed at all (see entries 11 and 12, respectively) under the
tested conditions. In the case of 4-pyridylboronic acid, the only
product isolated was the bismethoxy ester of 4-pyridylboronic
acid, which could potentially serve as a coupling partner itself for
the formation of 14. Unfortunately, we could not see any product
formation under the same conditions as described in Table 1 or 2
if the latter compound was used as a boronic ester source.
Changing reaction conditions such as temperature and time were
unsuccessful in delivering 14. Interestingly, more electron-rich
pyridine systems such as 2,6-(MeO)2pyridine boronic acid (see
entry 10 in Table 2) afforded the condensation product 12. This
example indicated that subtle electronic and steric effects might
be a key for the successful outcome of the condensation reaction.
To have a broader view about the structure−stability profile of
boratriazaroles, we resorted to the help of our in-house chemistry
automation laboratory, where a set of 47 different boronic acids
(aromatic, vinylic, and aliphatic) were screened (Scheme 2).
Amidrazone 1 was reacted with a specific boronic acid in DMF at
95 °C for 1 h, and the reaction was followed by LCMS analysis
(method omitting formic acid). Aliquots of the crude reaction
Figure 2. Comparison of ring geometry: (A) central borotriazarole ring
from compound 2; (B) pyrazole (taken from CCDC code ESOYIU);
(C) imidazole (CCDC code REPLIH). Non-hydrogen substituents
omitted for clarity.
yields root-mean-square deviations of just 0.057 and 0.056 Å,
respectively, and the three ring systems have virtually identical
bond distances and angles.
We speculated whether it might be possible to overcome the
observed susceptibility of 2 toward acid by increasing steric bulk
and varying electronic density around the boron center. At first,
we put substituents in both ortho positions of the phenyl ring,
which is linked to boron. The stability profiles of these
compounds were then qualitatively determined at different pH
values (5, 7, water, and 9) to get a basic understanding of the
structure−stability relationship. While the 2,6-bisfluoro com-
pound 4 showed a similar pH-dependent stability as 2, the 2,6-
bischloro compound 5 showed a much higher stability, with the
2,6-bismethyl compound 6 being the most stable under acidic
conditions (pH 5) (see the Supporting Information). The
Scheme 2. Procedure for the Automation Lab Study
B
dx.doi.org/10.1021/ol5032552 | Org. Lett. XXXX, XXX, XXX−XXX