Thermolysis of geminal diazides: Reagent-free synthesis of 3-hydroxypyridines

Article abstract of DOI:10.1021/acs.orglett.6b03475

An operationally simple protocol for the rapid and efficient construction of highly substituted 3-hydroxypyridines is presented. The thermally induced cyclization of easily constructed geminal diazides derived from β- ketoesters having an additional olefin moiety affords the title compounds in yields up to 97% under reagent-free conditions. The new method allows for the synthesis of preparative quantities of material. Additionally, the synthetic utility of the pyridine products for the synthesis of valuable heterocycles is described.

Full text of DOI:10.1021/acs.orglett.6b03475

Letter
pubs.acs.org/OrgLett
Thermolysis of Geminal Diazides: Reagent-Free Synthesis of
‑Hydroxypyridines
3
Hellmuth Erhardt, Kevin A. Kunz, and Stefan F. Kirsch*
̈
Organic Chemistry, Bergische Universitat Wuppertal, Gaußstraße 20, 42119 Wuppertal, Germany
*
S Supporting Information
ABSTRACT: An operationally simple protocol for the rapid and efficient
construction of highly substituted 3-hydroxypyridines is presented. The thermally
induced cyclization of easily constructed geminal diazides derived from β-
ketoesters having an additional olefin moiety affords the title compounds in yields
up to 97% under reagent-free conditions. The new method allows for the
synthesis of preparative quantities of material. Additionally, the synthetic utility of
the pyridine products for the synthesis of valuable heterocycles is described.
he intriguing chemical nature of the pyridine heterocycle1
Scheme 1. Strategies for the Synthesis of 3-Hydroxypyridines
T
in combination with its prominence in natural products
2
and pharmaceuticals has inspired chemists to develop new and
3
efficient methodologies toward its synthesis. In particular, 3-
hydroxypyridines have recently attracted attention due to their
promising biological activity (Figure 1). The motif can be
Figure 1. 3-Hydroxyypridines in nature and medicinal chemistry.
of dihydropyridines through highly regioselective hetero-Diels−
Alder cycloaddition followed by aromatization to the 3-
13
4
5
hydroxypyridine core.
found in nosiheptide and nocathiacine, both of which exhibit
antibiotic activity and are valuable entries to the family of
thiopeptide antibiotics. The 3-hydroxypyridine core is also part
We came in contact with this field of heterocyclic chemistry
as part of our ongoing efforts to employ geminal diazides as
14
6
valuable synthetic intermediates. More recently, we have
of caerulomycin B isolated from Streptomyces caeruleus and
15a
7
reported methods for the synthesis of geminal triazides and
16
persynthamide. Arguably the most known representative is
geminal diazides derived from 1,3-dicarbonyls. We also used
geminal diazides for the synthesis of azidomethylenebistriazoles
vitamin B6, an essential cofactor of the amino acid
8
metabolism. 3-Hydroxypyridines are also valuable starting
17
and their corresponding geminal tristriazoles. The thermolysis
of geminal diazides became of particular interest: Early studies
hinted at a great, but still undisclosed, potential for the
materials for the synthesis of furopyridines, many of which are
9
promising B-Raf inhibitors.
Several methods for the synthesis of 3-hydroxypyridines have
18
1
0
synthesis of nitrogen-containing heterocycles. By expansion
been developed, some of which are depicted in Scheme 1. In
particular, questions regarding the regioselective construction
of this heterocyclic core are still an ongoing important synthetic
challenge. For example, Renard and co-workers contributed to
this area via Kondrat’eva cycloaddition and subsequent cleavage
18c
of the works by Rank and Ogilvie, we showed that geminal
diazides are powerful starting materials for the preparation of
19
1
,3,4-oxadiazoles through thermolysis, as exemplified in eq 1.
To our surprise, conventional heating of geminal diazide 1a
11
with an additional olefin moiety in xylene did not provide the
of the resulting oxabicyclic products. Yanagisawa and co-
workers utilized ring-closing metathesis for the construction of
pyridinones, which afforded 3-hydroxypyridines upon oxida-
Received: November 21, 2016
1
2
tion. Moreover, Arndt and co-workers achieved the synthesis
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b03475
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
temperature. In addition, microwave irradiation resulted in a
marked decrease of decomposition, as judged from TLC
controls. We also note that unspecific intermolecular side
reactions may cause lowered yields at concentrations above 0.1
20
M; however, highly diluted reaction mixtures (<0.05 M) were
impractical due to the volume limitations we faced in our
microwave reactor with sealed 20 mL vials.
oxadiazole core. Instead, 3-hydroxypyridine 2a was isolated in
58% yield (Table 1, entry 1). The originally expected 1,3,4-
With the optimized reaction conditions at hand (Table 1,
entry 11), we further investigated the substrate scope of the
method and found that a good variety of substituted β−
ketoesters can be transformed into the corresponding 3-
hydroxypyridines in moderate to excellent yields (Scheme 2).
Table 1. Optimization of the Reaction Conditions for 2a
Scheme 2. Scope of the Thermolysis
a
entry
solvent
xylene
c (mol/L) temp (°C) yield (%)
comment
1
2
3
4
5
6
7
8
9
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.05
0.05
138
138
111
180
80
58
54
59
11
23
47
xylene
+ NaHCO3
toluene
1,2-Cl C H
2
6
4
benzene
n-octane
xylene
NMP
126
25
b
hν
130
82
dec
MeCN
12
33
97
70
10
11
12
Ph O
2
130
140
c
xylene
MW
xylene
138
a
b
c
Isolated yields. 254 nm irradiation. Microwave irradiation.
oxadiazole was not formed under the reaction conditions. We
now report that a promising range of 3-hydroxypyridines can be
generated from 2,2-diazido-3-oxohept-6-enoates through sim-
ple and reagent-free thermolysis. The method will likely
become a useful alternative to existing methods for the
synthesis of 3-hydroxypyridines, since the diazide starting
materials were previously found to be remarkably stable and are
easily accessed when the dicarbonyl precursors are stirred with
iodine and sodium azide in aqueous DMSO at room
1
6a
temperature.
Intrigued by our initial results on the formation of 3-
hydroxypyridine 2a, we conducted an expanded screening
experiment in various solvents and under different reaction
temperatures, as shown in Table 1. It was found that addition of
sodium bicarbonate to intercept possible acidic byproducts had
no influence on the product yield (entry 2). The use of toluene
gave rise to 2a in 59% (entry 3). 1,2-Dichlorobenzene led to a
unclean conversion at a reaction temperature of 180 °C and
afforded the product in poor 11% yield (entry 4). Benzene and
n-octane as well had no positive effect on the transformation
a
The reactions were carried out by refluxing a 0.05 M solution of the
corresponding geminal diazide under conventional heating for 2 h.
(
2
entries 5 and 6). It is worth mentioning that geminal diazide
a rapidly undergoes decomposition when stirred in xylene
under irradiation with light of a wavelength of 254 nm (entry
). NMP showed no traces of the desired product (entry 8),
whereas MeCN and Ph O afforded the product in 12% and
2
The presence of alkyl substituents at C4 (R = alkyl), as shown
with the examples of 2b and 2c, is well tolerated and led to 69%
and 48% yield, respectively. Benzyl ether 2d was obtained in
48% yield. As demonstrated by the formation of 2e in 72% and
2f in 68%, aromatics are fine under the reaction conditions, too.
Notably, the presented method allows for the preparation of
7
2
3
3% yield, respectively (entries 9 and 10). A major increase in
yield was observed when the reaction was carried out in xylene
at 140 °C with a concentration of 0.05 mol/L under microwave
conditions to afford the product in 97% isolated yield in a
remarkably clean reaction (entry 11). Conventional heating of a
2
biphenyls (R = aryl) as it was exemplified by the formation of
2g and 2h, which have been obtained in 62% and 81% yield.
Gratifyingly, bromo-substituted biphenyl 2i was accessed in
77% yield. When switching from terminal to internal olefins
with alkyl substituents (R3 = alkyl), the yields dropped
significantly. Pyridine 2j, for example, was obtained in poor
18% yield. Benzylated pyridine 2k was afforded in acceptable
0
.05 M solution yielded 2a in 70% (entry 12). As a general
trend, we noticed that microwave irradiation led, in a stipulated
time, to a significantly enhanced consumption of the starting
material, in comparison to traditional heating at the same
B
DOI: 10.1021/acs.orglett.6b03475
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
4
3
4% yield. The related heterocycles 2l and 2m were formed in
3% and 50% isolated yield. The synthesis of 3-hydroxypyr-
show their value as starting points for the facile synthesis of
attractive chemical entities (Scheme 4). Suzuki cross-coupling
idines was also possible with tert-butyl esters (e.g., 2n) and
amides (e.g., 2o), albeit with lower yields compared to the
analogous ethyl esters. We like to point out that all
transformations proceeded in an extraordinarily clean manner.
The isolation of the 3-hydroxypyridines was directly possible by
removing the solvent after completion of the reaction followed
by purification through column chromatography over silica.
Because of the reagent-free protocol, no aqueous workup was
necessary.
Scheme 4. Selected Modifications of 3-Hydroxypyridines
To show that the method allows for the synthesis of
preparative useful amounts of substance, the synthesis of 2a and
2
e was carried out with 5.05 and 2.44 g under conventional
heating and gave rise to the products in 70% and 53% isolated
yield. The reactions proceeded smoothly and without any kind
of hazardous or vigorous behavior in every case, thus rendering
the presented method safe and underlining the stable and easy
21,16a
to handle nature of the geminal diazide starting materials.
A rationale for the reaction was proposed and is depicted in
Scheme 3. We reasoned that the geminal diazide undergoes
Scheme 3. Rationale for the Formation of 3-
Hydroxypyridines
of 5, which was accessed from 2a in 82% yield with Tf O and
2
NEt , allowed for the synthesis of biphenyl 6 in 96% yield.
3
Furthermore, bromination of 2a with NBS gave rise to 4-
bromopyridine 7 in 77% yield. Subsequent Sonogashira cross-
coupling with an appropriate alkyne followed by intramolecular
cyclization turned out to be an excellent tool for the synthesis
of furo[2,3-c]pyridines (e.g., 8a with R = Ph in 85% and 8b
24
with R = TMS in 56% yield). We would like to highlight the
possibility for iododesilylation of compound 8b to furnish 9 in
7
9% yield (under concomitant replacement of the ethyl ester
25
with methanol). The furo[2,3-c]pyridines are interesting
compounds in medicinal chemistry due to their promising
activity as HIV-1 non-nucleoside reverse-transcriptase inhib-
26
27
itors and human toll-like receptor agonists. We consider 9
to be an attractive building block for biological studies due to
its ease of construction and vast possibilities for diversification.
In conclusion, we have presented a new method for the rapid
synthesis of highly substituted 3-hydroxypyridines by the
simple heating of geminal diazides. The ease of accessing the
diazide starting materials renders this method a flexible tool for
the generation of a broad range of the title compounds,
including pyridine cores with aliphatic, benzylic, and aromatic
groups. Hopefully, this methodological addition to the
chemistry of nitrogen-rich organic molecules inspires chemists
to continue research on the field of polyazidated compounds.
2
intramolecular [3 + 2]-Huisgen cycloaddition to form 1,2,3-Δ -
2
2
23
triazoline A. The unstable nature of A then allows for the
elimination of elemental nitrogen, thus forming B by a 1,2-
hydride shift to give imine C. Finally, elimination of hydrazoic
acid may lead to D, which after tautomerization gives rise to the
aromatic title compound. A strong indication for the
participation of an imine intermediate was found by conducting
the thermolysis of monoazide 3. In the absence of the second
azide functionality acting as a leaving group, the only product
that was detectable was the imine 4; the sequence was stopped
at this stage without the possibility of reacting under
aromatization. On further notice, all reactions were accom-
panied by the smooth evolution of gas bubbles which can be
rationalized by the loss of nitrogen during the formation of
intermediate B. After the reaction had reached completion, no
IR-signal characteristic for azides was present in the crude
mixture, thus implying a complete degeneration of all azide
units (including the possibly formed hydrazoic acid) under the
reaction conditions.
ASSOCIATED CONTENT
Supporting Information
■
*
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b03475.
Experimental and spectral details for all new compounds
and all reactions (PDF)
AUTHOR INFORMATION
Corresponding Author
■
To provide insight into the use of the obtained 3-
hydroxypyridines, we then engaged in subsequent studies to
*E-mail: sfkirsch@uni-wuppertal.de.
C
DOI: 10.1021/acs.orglett.6b03475
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
ORCID
Letter
potentially hazardous compounds that should always be handled
with great care and appropriate safety equipment.
Stefan F. Kirsch: 0000-0003-2628-8703
Notes
(
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alkene under the formation of imines is known. For representative
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23) (a) Huisgen, R. Angew. Chem., Int. Ed. Engl. 1963, 2, 565.
b) Wolff, L. Justus Liebigs. Ann. Chem. 1912, 394, 23.
́
The authors declare no competing financial interest.
1
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DOI: 10.1021/acs.orglett.6b03475
Org. Lett. XXXX, XXX, XXX−XXX