One step conversion of heteroaromatic-N-oxides to imidazolo-heteroarenes

Article abstract of DOI:10.1021/jo702038g

(Chemical Equation Presented) Various pyridine-, quinoline-, isoquinoline-, and pyrimidine-N-oxides were converted to their corresponding α-imidazoloheteroarenes in good yield by treatment with sulfuryl diimidazole in nonpolar solvents at elevated tempera

Full text of DOI:10.1021/jo702038g

One Step Conversion of
Heteroaromatic-N-Oxides to
Imidazolo-Heteroarenes
John M. Keith
Johnson & Johnson Pharmaceutical Research and DeVelopment
L.L.C., 3210 Merryfield Row, San Diego, California 92121
jkeith@prdus.jnj.com
ReceiVed September 19, 2007
FIGURE 1. Possible strategies for the activation and substitution of
N-oxides with potential side reactions shown.
Various pyridine-, quinoline-, isoquinoline-, and pyrimidine-
N-oxides were converted to their corresponding R-imida-
zoloheteroarenes in good yield by treatment with sulfuryl
diimidazole in nonpolar solvents at elevated temperatures.
FIGURE 2. Possible mechanism for conversion of heteroarene-N-
oxides to R-imidazolo-heteroarenes with sulfuryl diimidazole.
With our continuing interest in transformations of potential
use to the pharmaceutical industry,1 we wished to develop an
alternate method for the introduction of imidazole functionality
R- to heteroarene nitrogens. Typically, imidazole is introduced
to electron-poor heteroarenes via substitution of a halide at
elevated temperatures2 or through the use of a copper catalyst.3,4
The heteroarene halide, in turn, can be prepared by halogenation
of an N-oxide precursor5 with subsequent deoxygenation,6-9
deoxygenative halogenation,10 direct metalation of an N-oxide
followed by quenching with an electrophilic halide source,11 or
through the conversion of an R-hydroxyl group with an oxyphilic
halide source such as SOCl212 or POCl3.13 We felt it was feasible
to circumvent the need for the halide through activation of
heteroarene-N-oxides to nucleophilic attack with concomitant
elimination of the oxygen functionality, giving both a more
concise and orthogonal approach to the introduction of imida-
zole. Such a transformation could be approached in several
ways (Figure 1): (1) the N-oxide could be converted to an
isolable salt14,15 and then treated with imidazole; (2) the N-oxide
could be activated in situ16 and treated with imidazole; or (3)
the N-oxide could be treated with an electrophile with imidazole
as a labile substituent. Each of these approaches is precedented
in the literature, but they have different potential propensities
to give side products. Activation of an N-oxide by either
approach (1) or (2) has the potential to give alternate pro-
ducts incorporating imidazole. In eq 1, the R′ group on the
N-oxide could be transferred to imidazole thus consuming the
activating agent and nucleophile. In other instances, the nu-
cleophile may be basic enough to promote the oxidation of
the R′ group, thus consuming the N-oxide.17 In eq 2, the
electrophilic substituent on the N-oxide could be transferred
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10.1021/jo702038g CCC: $40.75 © 2008 American Chemical Society
Published on Web 12/08/2007
J. Org. Chem. 2008, 73, 327-330
327

TABLE 1. Substrate Scope
to the nucleophile, thus slowing or shutting down the reaction.18
The strategy found in eq 3 should avoid the possible side
reactions found in eqs 1 and 2, but the reaction may proceed
more slowly because the leaving group on the electrophile is
imidazole, a less labile substituent than a halide, sulfonate, or
phosphate.
With the above issues in mind, we elected to explore the
strategy inherent to eq 3 (Figure 2). Fortunately, the com-
mercially available sulfuryl diimidazole is an electrophilic, easily
handled solid and has imidazole as the only putative counterion,
thus obviating the need for an exogenous base. For these reasons,
we elected to use sulfuryl diimidazole for the studies described
herein.
but dissolved readily in MeOH or water. We believe the residue
is likely to be a complex between the product (and, in some
cases, the starting material) and sulfur trioxide. Several pieces
of data support this possibility: no gas evolution is apparent
during the course of reaction;20 pyridine/sulfur trioxide com-
plexes are known;21 and we isolated and characterized a
chromatographically stable product/SO3 complex.22 The overall
mechanism of the reaction likely resembles the one shown in
Figure 2.23
(19) We also obtained a small amount (1%) of dimeric product (A). A
similar product was obtained in a previous project (ref 1a) utilizing sulfuryl
chloride.
Initial optimization of reaction conditions was conducted
using 4-phenylpyridine-N-oxide as the substrate. Heating a
solution of 4-phenylpyridine-N-oxide and sulfuryl diimidazole
in toluene at reflux resulted in complete consumption of starting
material after 6 h, giving a good yield (76%) of 1.19 During the
course of reaction, a dark oily residue formed on the sides of
the flask. The residue hardened upon cooling and was insoluble
in nonpolar organic solvents (CH2Cl2, EtOAc, CH3CN, etc.)
(20) Heating a mixture of solid N-oxide with sulfuryl diimidazole to
melting (120 °C) resulted in sudden reaction with potentially dangerous
concomitant release of gas (presumably SO3). Although product was formed
under these conditions (54%), such neat preparations should be avoided.
(21) Barnes, R. S.; Harris, J. E. G.; Thomas, J. U.S. Patent 1921497,
1933.
(18) Chen, Z-C.; Stang, P. Tett. Lett. 1984, 25, 3923-3926.
328 J. Org. Chem., Vol. 73, No. 1, 2008

TABLE 2. Substrates Giving Atypical Products
FIGURE 3. Proposed explanation of product distribution based on
work up procedure.
and m-xylene worked equally well as solvents for reactions run
at 130 °C. Imidazole generally substituted the position R to the
ring nitrogen. Pyridine-N-oxides possessing alkyl and halide
substitution in the 3-position moderately favored substitution
at the 6-position (entries 11 and 12). When the 3-position
possesses a methoxy group, substitution at the 2-position is
favored (entry 4). Functionality in the 2-position of the N-oxide
results in slower reaction (entries 5 and 7) while retaining
selectivity for substitution at the 6-position. Only 2-(2-pyridyl)-
pyridine-N-oxide (entry 9) yielded a small amount of product
resulting from substitution of the 4-position (12). Quinoline-,
isoquinoline-, and pyrimidine-N-oxide (entries 8, 10 and 13)
were each effectively substituted under the standard reaction
conditions.
Some substrates gave atypical products or product mixtures
(Table 2).24 An attempt to force substitution to the 4-position
of 2,6-lutidine-N-oxide instead resulted in very slow substitution
of one of the methyl groups (Table 2, entry 1). Similarly, with
both the 4- and the 6-positions of pyrimidine-N-oxide blocked
by methyl groups (Table 2, entry 2), methyl group substitution
(21) competed with substitution of the 2-position (22). 3-Cy-
anopyridine-N-oxide gave substitution products 23-25 in all
but the 5-position due to the strong directing effects of the nitrile
(entry 3). Additionally, a small amount of methyl imidate ester
(26) was isolated chromatographically. This product was initially
something of a mystery as we were uncertain whether metha-
nolysis was occurring during the purification process or,
seemingly less likely, during workup. Methanolysis was even
more pronounced with 4-cyanopyridine-N-oxide (Table 2, entry
4) as the substrate. Both the methyl imidate (28) and its
hydrolysis product, the primary amide (29), were obtained. In
this case, we were able to determine 28 was formed during the
workup procedure in which we rinsed the reaction vessel with
methanol and added the mixture to 1 N NaOH. The formation
of products resulting from methanolysis could be avoided by
rinsing the flask with 1 N NaOH, giving rise to greatly improved
yields of 27 (entry 5). We suspect the products obtained after
workup reflect the electronic nature of the product/SO3 complex
(Figure 3). The nitrile in the product/SO3 complex should be
more electrophillic relative to product alone. As a result of this
activation, the relatively soft nucleophile methanol reacts with
the nitrile (a soft electrophile) to give the methyl imidate ester.
Conversely, treatment of the crude reaction mixture with NaOH
(a hard nucleophile) most likely results in hydroxide ion
attacking the highly electrophillic (i.e., hard) sulfur atom giving
Table 1 shows the results and reaction conditions for a variety
of non-, mono-, and disubstituted heteroarene-N-oxides. Most
electron-rich N-oxides went to completion within 24 h whereas
electron poor and sterically encumbered substrates required
longer reaction times and higher temperatures. Chlorobenzene
(22) Only the SO3 complex of product 5 was isolated and characterized,
but such complexes were detected by M.S. with many of the substrates
examined.
(23) See ref 1a.
(24) For discussion and examples of poor substrates, please see the
Supporting Information.
J. Org. Chem, Vol. 73, No. 1, 2008 329

N NaOH25 and added to the separatory funnel. The mixture in the
separatory funnel was then mixed vigorously and then extracted
with methylene chloride (300 mL × 2), and the organic layer was
dried (MgSO4), filtered, and evaporated to dryness to give the crude
product. Chromatographic purification (silica gel, eluting with
0-5% 2 N NH3 in MeOH/CH2Cl2) gave 565.1 mg (79%) of
reasonably pure desired product. Further purification by HPLC (X-
Terra C18, 10-100% CH3CN/H2O w/0.05% TFA) gave product as
a TFA salt.
sulfate ion thus freeing the desired product. Once the product
has been decomplexed from SO3, the nitrile becomes more
resistant to solvolysis.
In conclusion, we have developed a convenient 1-step
procedure for the conversion of heteroarene-N-oxides to R-imi-
dazoloheteroarenes in fair to excellent yield through the action
of sulfuryl diimidazole at elevated temperatures.
Experimental Section
Acknowledgment. I thank Heather McAllister for analytical
work performed in support of this project.
Procedure for Preparing Compound 27. To a 100 mL round-
bottomed flask were added 507 mg (4.22 mmol) of 4-cyanopyridine-
N-oxide, 1.239 g (6.25 mmol; 1.5 equiv) of sulfuryl diimidazole,
and an appropriate solvent (41 mL chlorobenzene; 0.1 M). The
flask was fitted with a reflux condenser, the system was purged
with nitrogen, and the mixture was heated with stirring at 130 °C
until consumption of N-oxide was complete (3 days) as determined
by TLC or HPLC. As the reaction proceeded, a dark precipitate
formed on the sides of the flask. Once conversion of N-oxide was
complete, the reaction mixture was added to a separatory funnel
containing 1 N NaOH. The residue in the flask was taken up in 1
Supporting Information Available: 1H and 13C NMR spectra,
HPLC chromatographs, melting points, experimental procedures,
and tabulated spectral data for all prepared compounds. This
materialisavailablefreeofchargeviatheInternetathttp://pubs.acs.org.
JO702038G
(25) Alternatively, the flask may be rinsed with MeOH when the N-oxide
substrate does not possess a nitrile.
330 J. Org. Chem., Vol. 73, No. 1, 2008