One-step conversion of pyridine N-oxides to tetrazolo[1,5-a]pyridines

Article abstract of DOI:10.1021/jo061819j

(Chemical Equation Presented) Pyridine N-oxides were converted to tetrazolo[1,5-a]pyridines in good to excellent yield by heating in the presence sulfonyl or phosphoryl azides and pyridine in the absence of solvent. Various sulfonyl and phosphoryl azides were screened for reactivity under a standard set of conditions. Diphenyl phosphorazidate was the most convenient reagent and gave high yields. Reaction optimization, scope, and scalability are discussed.

Full text of DOI:10.1021/jo061819j

One-Step Conversion of Pyridine N-Oxides to
Tetrazolo[1,5-a]pyridines
John M. Keith
Johnson & Johnson Pharmaceutical Research & DeVelopment,
L.L.C. 3210 Merryfield Row, San Diego, California 92121
jkeith@prdus.jnj.com
ReceiVed September 1, 2006
FIGURE 1. Tetrazolopyridines as intermediates.
Pyridine N-oxides were converted to tetrazolo[1,5-a]pyridines
in good to excellent yield by heating in the presence sulfonyl
or phosphoryl azides and pyridine in the absence of solvent.
Various sulfonyl and phosphoryl azides were screened for
reactivity under a standard set of conditions. Diphenyl
phosphorazidate was the most convenient reagent and gave
high yields. Reaction optimization, scope, and scalability are
discussed.
8
the aminopyridine via a Staudinger reaction. Cycloaddition with
9
terminal alkynes to give the corresponding triazole has also
been demonstrated. Reactivity not typical of azides includes
reduction of the pyridine ring to give aliphatic tetrazoles and
alkylation or arylation of the tetrazole to give otherwise
difficult to access N-substituted bicyclic tetrazoles.
10
11
12
Tetrazolopyridines are typically prepared by heating a 2-ha-
lopyridine in the presence of NaN3 in a polar solvent. The
precursor halopyridine is typically prepared from the pyridone
or N-oxide or by direct halogenation of the pyridine ring.
There were two reports of tetrazolopyridines prepared directly
13
14
1
5
16
Organic azides are especially versatile functional groups.
1
Azides are commonly used as precursors to primary amines,
17
from the N-oxides using toluenesulfonyl azide (TsN3) and
2
3
nitrenes, and triazoles. Azides adjacent to a heteroaromatic
nitrogen atom exist in equilibrium with the corresponding
tetrazole. Substituents on the heteroaromatic ring can influence
1
8
diphenyl phosphorazidate (DPPA), but neither examined the
reaction in any depth. We elected to reexamine the conversion
of pyridine N-oxides to tetrazolopyridines with the goals of
optimizing reaction conditions, determining substrate scope, and
developing the process for multigram scale.
4
5
the ratio of products at equilibrium, but in most instances, the
tetrazole is the predominant species present. Despite the
dominance of the tetrazole in the azide/tetrazole equilibrium,
reactivity typical of azides can be observed. Tetrazolopyridines,
Figure 1, can be converted to the pyridylnitrene under both
(
7) (a) Reisinger, A.; Koch, R.; Wentrup, C. J. Chem. Soc., Perkin Trans.
1 1998, 15, 2247-2250. (b) Kuzaj, M.; Luerssen, H.; Wentrup, C. Angew.
6
7
thermal and photochemical conditions and can be reduced to
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B. J. THEOCHEM 2001, 535 199-215. (b) Kanyalkar, M.; Coutinho, E.
C. Tetrahedron 2000, 56, 8775-8777. (c) Cmoch, P.; Stefaniak, L.; Webb,
G. A. Magn. Reson. Chem. 1997, 35, 237-242. (d) Guimon, C.; Khayar,
S.; Pfister-Guillouzo, G.; Claramunt, R. M.; Elguero, J. Spectrosc. Lett.
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981, 14, 747-753. (e) Boyer, J. H.; Miller, E. J., Jr. J. Am. Chem. Soc.
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Heterocycl. Chem. 1967, 4, 375-376.
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10.1021/jo061819j CCC: $33.50 © 2006 American Chemical Society
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J. Org. Chem. 2006, 71, 9540-9543
Published on Web 11/14/2006

TABLE 1. Influence of Temperature, Base, and Sulfonyl
Activating Groups on the Yield of 7-Phenyltetrazolo[1,5-a]pyridine
FIGURE 2. Reaction mechanism.
To affect the conversion of pyridine N-oxides to tetrazolo-
[1,5-a]pyridines, we examined a number of activating groups
(sulfonyl, sulfuryl, phosphonyl, and phosphoryl halides) in the
presence of trimethylsilyl azide (TMSN3). As we anticipated
the reaction proceeding via a mechanism similar to that shown
in Figure 2, we focused on electrophiles that could strongly
activate the N-oxide to both nucleophilic attack and elimination.
Reactions were run neat at elevated temperature under a
nitrogen atmosphere with a fixed reaction time of 24 h.
Metathesis between TMSN3 and the activating group was
evident at 75 °C, as TMSCl would distill out (bp ) 57-59 °C)
of the reaction mixture. The reaction mixtures were typically
kept at 75 °C for 30 min to 4 h to allow for distillation of the
TMSCl. Table 1 shows the results with sulfur-based activating
groups. Interestingly, most of the sulfur-based reagents affect
the desired transformation to some degree. Reaction temperature
and the presence of base had a large impact on reaction outcome.
Reactions run at higher temperature (100 vs 75 °C) gave higher
yields. Likewise, the addition of 2 equiv of pyridine was found
to be beneficial to the yield in most19 cases examined, but 5
equiv of pyridine did not result in higher yields (compare entries
7
vs 8, Table 1). N-Methylimidazole (NMI) was not an effective
base for this reaction (compare entries 1-3, Table 1). The best
chemical yields were obtained with toluenesulfonyl chloride
(TsCl, entry 6, Table 1), 2-fluorophenylsulfonyl chloride (entry
1
8, Table 1), and phenylsulfonyl fluoride (entry 25, Table 1)
as the activating reagents.
We next examined phosphoryl azides in the conversion of
N-oxides to tetrazolopyridines. With the exception of com-
(19) Entries 1 and 3 showed small differences in yield; adding base to
MsCl (entries 9 and 10) gave a tarry mixture containing some reduced
product (see below).
(20) Upon addition of ClCH2SO2Cl to a mixture of N-oxide and TMSN3,
the mixture began to effervesce immediately. Analysis of the reaction
mixture revealed the pyridine N-oxide was being reduced to the pyridine.
Conducting the experiment in the absence of TMSN3 and base at 90 °C,
resulted in clean, quantitative reduction of the N-oxide. Such reductions
have been seen previously with alkylsulfonyl chlorides in the presence of
Et3N, but ClCH2SO2Cl, like phenylmethanesulfonyl chloride, does not
appear to require base to act as a reducing agent, possibly as a result of it
more readily forming the sulfene. A small amount of reduced N-oxide was
detected when MsCl was used as the activating group; see: Morimoto, Y.;
Kurihara, H.; Shoji, T.; Kinoshita, T. Heterocycles 2000, 53, 1471-1474.
a
All yields are post-chromatography: reactions run on a 100 mg scale
30
relative to N-oxide: 75-100 ) heating at 75 °C for 30 min before heating
to 100 °C; 75-100 heating at 75 °C for 4 h before heating to 100 °C.
4
mercially available diphenyl phosphorazidate, phosphoryl azides
were prepared in situ from the corresponding phosphoryl
chloride and TMSN3. Most were effective mediators of the
(
21) The heterogeneity of the reaction mixture may have been responsible
for the low to nonexistent yields obtained with the nitrophenylsulfonyl
chlorides.
J. Org. Chem, Vol. 71, No. 25, 2006 9541

TABLE 2. Influence of Temperature, Base, and Phosphonyl
Activating Groups on the Yield of 7-Phenyltetrazolo[1,5-a]pyridine
TABLE 3. Substrate Scope with DPPA as Activating Group
a
All yields are post-chromatography: reactions run on a 100 mg scale
relative to N-oxide.
desired transformation except for diethyl chlorophosphate and
chlorodiphenylphosphine oxide.23 The three best reagents in this
series were DPPA (entry 4), bis(2,2,2-trichloroethyl) chloro-
phosphate (entry 8), and bis(3,4-dichlorophenyl) chlorophos-
phate (entry 9), all giving comparable yields. We further
examined the use of DPPA at higher temperatures (entries 5
and 6) and observed incremental increases in yield, with a
quantitative yield obtained at 120 °C with our model substrate.
(
22) Sulfuryl chloride (Table 1, entries 21 and 22) gave some desired
product, but also a small amount (5 %) of the dehydratively coupled product
2), possibly arising via the mechanism shown below. Differentially
(
functionalized bipyridyls could be very useful intermediates in the synthesis
of metal ligands. We are presently pursuing the optimization of dehydratively
coupling pyridine N-oxides.
a
All yields are post-chromatography: reactions run on a 100 mg scale
relative to N-oxide. b The reaction was run for 48 h.
(23) Diethyl chlorophosphate is probably succeptible to nucleophilic
attack by azide ion to give EtN3 and a less electrophilic monoalkyl
azidophosphate. Chlorodiphenylphosphine oxide formed a chromatographi-
cally stable azide, but it was unreactive under our standard conditions.
From the data in Tables 1 and 2, we elected to examine the
scope of this reaction using DPPA as our activating agent and
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542 J. Org. Chem., Vol. 71, No. 25, 2006

azide source as it gave excellent yields24 of product and was
the most convenient to use.25 The substrate scope is illustrated
in Table 3.
Simple pyridine N-oxides were effective substrates for this
reaction. Alkyl- and aryl-substituted pyridine N-oxides gave
good to excellent yields of the corresponding tetrazolo[1,5-a]-
pyridine. Much lower reactivity was observed with 4-methoxy-
pyridine N-oxide, although allowing the reaction to proceed for
4
3
8 h did give useful yields of product (entry 7). Halides in the
-position gave a mixture of products favoring substitution at
FIGURE 3. Optimization for larger scale reactions. Reactions were
run on a 0.5 g scale.
the more electrophilic 2-position over the 6-position (pyridine
numbering: entries 10 and 11). The converse was true when
the 3-substituent was electron donating (entry 12). Halides in
the 2- and 4-positions gave complex product mixtures, possibly
resulting from competing SNAr processes. As the stability of
the products was a concern,26 the thermal stability of each of
the product tetrazolopyridines was examined by taking the
melting point. All of the products exhibited narrow melting point
ranges without any obvious sign (color change, gas evolution)
of decomposition.
pyridine N-oxide to tetrazolo[1,5-a]pyridine on a 10 g scale.
Gratifyingly, the reaction gave 10.92 g (86%) of the desired
product as a readily crystallizable white solid.
In conclusion, we have developed a methodology for the
direct conversion of pyridine N-oxides to tetrazolo[1,5-a]-
pyridines in high yield under solvent free conditions. The
process is easily scaled up without significant diminishment of
yield.
In anticipation of developing a multigram procedure for this
transformation, we first examined the amount of DPPA required
for the reaction. We recognized that 5 equiv of DPPA, while
satisfactory for very small-scale reactions lacking solvent, would
be undesirable for large-scale processes. Using 4-phenylpyridine
N-oxide as our model substrate, we examined the reaction with
reduced equivalents of DPPA (Figure 3). We found that 2 equiv
of DPPA still gave excellent yields of product (90% vs quant
with 5 equiv of DPPA) without extending the reaction time.
With these results in hand, we examined the conversion of
Experimental Section
General Procedure Using DPPA. To a conical flask were added
a stirbar, N-oxide (1 equiv), DPPA (2-5 equiv), and pyridine (2
equiv). The flask was purged with nitrogen and heated to 120 °C
for 24 h. Direct chromatographic purification (0-2% of 2 N NH
3
in MeOH/CH Cl ) of the reaction mixture gave the pure product.
2
2
Acknowledgment. We warmly thank DJ Tognarelli and
Jiejun Wu for their effort in generating some of the analytical
data for this project and Chris Mapes for generously providing
a sample of 3,4-dimethylpyridine N-oxide.
(24) Though the sulfonyl halides gave comparable yields under some
conditions, the products obtained from those reactions possessed trace
amounts of color-imparting impurities making the products slightly yellow
to orange as compared to bright white when DPPA was used.
Supporting Information Available: 1H and 13C NMR, HPLC,
and IR spectra, experimental procedures, and tabulated spectral data
for all prepared compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
(
25) Trapping the TMSCl generated in the reaction mixture was a
concern, especially for large-scale preparations.
26) A reaction containing 4-nitropyridine N-oxide began to effervesce
at 75 °C, and heating was stopped for perceived potential safety reasons.
(
JO061819J
J. Org. Chem, Vol. 71, No. 25, 2006 9543