Magnesiation of pyridine N-oxides via iodine or bromine-magnesium exchange: A useful tool for functionalizing pyridine N-oxides

Article abstract of DOI:10.1021/jo802172f

Iodo- or 2-bromopyridine N-oxides were readily magnesiated with i-PrMgCl ? LiCl via the iodine or bromine-magnesium exchange. The bromine adjacent to pyridine N-oxide (at the 2- or 6-position) can be regioselectively magnesiated in the presence of other position substituted halogens. This method was tested in various substituted pyridine N-oxide systems, and has been successfully applied to the total synthesis of caerulomycins E and A.

Full text of DOI:10.1021/jo802172f

nitration, halogenation, and cyanation.1 For example, consider-
able efforts have been reported recently in the conversion of
the N-oxides into (a) 2-aminopyridine with Ts2O-tBuNH2
followed by in situ deprotection with TFA,5 (b) 2-aminopyridine
amides with imidoyl chlorides,6 (c) tetrazolopyridines with
sulfonyl or phosphoryl azides7 and imidazolopyridines with
sulfuryl diimidazole,8 (d) 2-alkyl, alkynyl, and arylpyridines
with Grignard reagents,9 and (e) 3-(2-hydroxyaryl)pyridines with
arynes.10 It is noteworthy that pyridine N-oxides also served as
an ideal choice to direct C-H functionalization of the pyridine
ring.11 Currently the pyridine N-oxides preparation is mainly
focused on the oxidation of corresponding pyridine analogues.
To this end, an alternative approach was described herein to
prepare the pyridine N-oxide derivatives via direct functional-
ization without deoxygenation.
Magnesiation of Pyridine N-Oxides via Iodine or
Bromine-Magnesium Exchange: A Useful Tool
for Functionalizing Pyridine N-Oxides
Xin-Fang Duan,* Zi-Qian Ma, Fang Zhang, and
Zhan-Bin Zhang
Department of Chemistry, Beijing Normal UniVersity,
Beijing, 100875, China
xinfangduan@Vip.163.com
ReceiVed September 29, 2008
Metalation of substituted pyridines has been well investi-
gated;12 however, only limited examples were reported regarding
the metalation of pyridine N-oxides, through either lithium or
zinc reagents.13,14 One of the challenges in lithiation with use
of n-BuLi, LDA, or LTMP is unwanted deprotonation of the
side chain if it is present at the pyridine N-oxide 2- or
(4) (a) Balzarini, J.; Keyaerts, E.; Vijgen, L.; Vandermeer, F.; Stevens, M.;
Clercq, E. D.; Egberink, H.; Ranst, M. V. J. Antimicrob. Chemother. 2006, 57,
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Chem. 2007, 72, 4554.
(6) (a) Manley, P. J.; Bilodeau, M. T. Org. Lett. 2002, 4, 3127. For a similar
conversion of quinoline N-oxides, see: (b) Couturier, M.; Caron, L.; Tumidajski,
S.; Jones, K.; White, T. D. Org. Lett. 2006, 8, 1929.
(7) Keith, J. M. J. Org. Chem. 2006, 71, 9540.
(8) Keith, J. M. J. Org. Chem. 2008, 73, 327.
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(b) Andersson, H.; Wang, X.; Bjo¨rklund, M.; Olsson, R.; Almqvista, F.
Tetrahedron Lett. 2007, 48, 6941. (c) Chung, J. Y. L.; Cvetovich, R. J.;
McLaughlin, M.; Amato, J.; Tsay, F.-R.; Jensen, M.; Weissman, S.; Zewge, D.
J. Org. Chem. 2006, 71, 8602.
Iodo- or 2-bromopyridine N-oxides were readily magnesiated
with i-PrMgCl· LiCl via the iodine or bromine-magnesium
exchange. The bromine adjacent to pyridine N-oxide (at the
2- or 6-position) can be regioselectively magnesiated in the
presence of other position substituted halogens. This method
was tested in various substituted pyridine N-oxide systems,
and has been successfully applied to the total synthesis of
caerulomycins E and A.
(10) Raminelli, C.; Liu, Z.; Larock, R. C. J. Org. Chem. 2006, 71, 4689.
(11) (a) Campeau, L.-C.; Rousseaux, S.; Fagnou, K. J. Am. Chem. Soc. 2005,
127, 18020. (b) Leclerc, J.-P.; Fagnou, K. Angew. Chem., Int. Ed 2006, 45, 7781.
(c) Do, H.-Q.; Daugulis, O. J. Am. Chem. Soc. 2007, 129, 12404. (d) Kanyiva,
K. S.; Nakao, Y.; Hiyama, T. Angew. Chem., Int. Ed. 2007, 46, 8872. (e)
Campeau, L.-C.; Schipper, D. J.; Fagnou, K. J. Am. Chem. Soc. 2008, 130, 3266.
(f) Campeau, L.-C.; Me´gan, B.-L.; Leclerc, J.-P.; Villemure, E.; Gorelsky, S.;
Fagnou, K. J. Am. Chem. Soc. 2008, 130, 3276. (g) Cho, S. H.; Hwang, S. J.;
Chang, S. J. Am. Chem. Soc. 2008, 130, 9254. For a similar reaction of
N-iminopyridinium ylides, see: (h) Larive´e, A.; Mousseau, J. J.; Charette, A. B.
J. Am. Chem. Soc. 2008, 130, 52.
(12) For reviews, see: (a) Chinchilla, R.; Na´jera, C.; Yus, M. ARKIVOC 2007,
12, 152. (b) Mulvey, R.; Mongin, F.; Uchiyama, M.; Kondo, Y. Angew. Chem.,
Int. Ed. 2007, 46, 3802. (c) Schlosser, M.; Mongin, F. Chem. Soc. ReV. 2007,
36, 1161. (d) Mongin, F.; Que´guiner, G. Tetrahedron 2001, 57, 4059. For a
recent report, see: (e) Seggio, A.; Chevallier, F.; Vaultier, M.; Mongin, F. J.
Org. Chem. 2007, 72, 6602.
(13) (a) Denmark, S. E.; Fan, Y. Tetrahedron: Asymmetry 2006, 17, 687.
(b) Tre´court, F.; Gervais, B.; Mongin, O.; Gal, L. C.; Mongin, F.; Que´guiner,
G. J. Org. Chem. 1998, 63, 2892. (c) Mongin, O.; Rocca, P.; Dumont, L. T.;
Tre´court, F.; Marsais, F.; Godard, A.; Que´guiner, G. J. Chem. Soc., Perkin Trans.
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1989, 30, 183. (e) Abramovitch, R. A.; Saha, M.; Smith, E. M.; Coutts, R. T.
J. Am. Chem. Soc. 1967, 89, 1537. For an example of lithiation of 2-bromopy-
ridine N-oxide through bromine-lithium exchange with n-BuLi, see: (f)
Takahashi, T.; Koga, H.; Sato, H.; Ishizawa, T.; Taka, N. Heterocycles 1995,
41, 2405. For an example of the lithiation of pyrazole N-oxide, see: (g) Paulson,
A. S.; Eskildsen, J.; Vedsø, P.; Begtrup, M. J. Org. Chem. 2002, 67, 3904.
(14) Hlavinka, M. L.; Hagadorn, J. R. Organometallics 2007, 26, 4105.
Pyridine N-oxide1 has received wide attention as a synthetic
intermediate, oxidant,2 catalyst, and ligand.3 In addition, some
of the related compounds are also of important biological or
pharmaceutical activities.4 Pyridine N-oxides have been utilized
as an important tool to functionalize the pyridine ring including
(1) (a) Katritzky, A. R.; Lagowski, J. M. Heterocyclic N-oxides; Methuen:
London, UK, 1967. (b) Albini, A.; Pietra, S. Heterocyclic N-oxides; CRC Press
Wolfe Publishing: London, UK, 1991. (c) Katritzky, A. R.; Lam, J. N.
Heterocycles 1992, 33, 1011. (d) Albini, A. Synthesis 1993, 263. (e) Youssif, S.
ARKIVOC 2001, 242 (i).
(2) Ito, R.; Umezawa, N.; Higuchi, T. J. Am. Chem. Soc. 2005, 127, 824,
and references cited therein.
(3) Chiral pyridine N-oxides and their analogues are useful catalysts or ligands
for asymmetric catalysis, for the most recent examples, see: (a) Malkov, A. V.;
Ram´ırez-Lo´pez, P.; Biedermannova´, L.; Dufkova´, L.; Kotora, M.; Zhu, F.;
Kocovsky´, P. J. Am. Chem. Soc. 2008, 130, 5341. (b) Chelucci, G.; Belmonte,
N.; Benaglia, M.; Pignataro, L. Tetrahedron Lett. 2007, 48, 4037. For reviews,
see: (c) Malkov, A. V.; Kocovsky´, P. Eur. J. Org. Chem. 2007, 29. (d) Kwong,
H. L.; Yeung, H. L.; Yeung, C. T.; Lee, W. S.; Lee, C. S.; Wong, W. L. Coord.
Chem. ReV. 2007, 251, 2188. (e) Chelucci, G.; Murineddu, G.; Pinna, G. A.
Tetrahedron: Asymmetry 2004, 15, 1373. (f) Malkov, A. V.; Kocovsky´, P. Curr.
Org. Chem. 2003, 7, 1737. (g) Chelucci, G.; Thummel, R. P. Chem. ReV. 2002,
102, 3129.
10.1021/jo802172f CCC: $40.75
Published on Web 12/04/2008
2009 American Chemical Society
J. Org. Chem. 2009, 74, 939–942 939

TABLE 1. Magnesiation of Iodo- or 2-Bromopyridine N-Oxide Derivativesa
a The reactions were carried out at -40 °C for entries 1-17 and -60 °C for entries 18-20. b Isolated yield. c The Grignard reagent was
transmetalated with CuI ·2LiCl before reacting with allyl bromide. d Isolated yield of 2j. e The oxides were hardly dissoluble in THF and CH2Cl2 was
used as a cosolvent. f 2.1 equiv of i-PrMgCl·LiCl was used during the exchange reaction.
6-position.14,15 To this regard, Grignard reagent was employed
here as an alternative metalation agent helping to improve
chemoselectivity and eliminate the aforementioned side prod-
ucts. Magnesiation of pyridine N-oxides was carried out through
either iodine or bromine-magnesium exchange in the Knochel’s
manner.16
2-Iodopyridine N-oxide (1a) and PhCHO were chosen as the
substrates, and an array of Grignard reagents were tested,
including i-PrMgBr, i-PrMgCl, and i-PrMgCl·LiCl. Initial
(15) (a) Garc´ıa-Flores, F.; Flores-Michel, L. S.; Juaristi, E. Tetrahedron Lett.
2006, 47, 8235. (b) Abramovitch, R. A.; Smith, E. M.; Knaus, E. E.; Saha, M.
J. Org. Chem. 1972, 37, 1690.
940 J. Org. Chem. Vol. 74, No. 2, 2009

TABLE 2. Regioselective Magnesiation of Di- or
SCHEME 1. Total Synthesis of Caerulomycins E and A
Tribromopyridine N-Oxidesa
a The reactions were carried out at -40 °C. b Isolated yield. c No
2-bromopyridine N-oxide was observed in our hands. d The Grignard
reagent was transmetalated with CuI ·2LiCl before reacting with allyl
bromide.
groups, such as amide or cyano (Table 1, entries 18-20). Unlike
the lithiation conditions,14 no deprotonation of a 2(or 6)-methyl
group was observed (Table 1, entries 2, 15, and 20). Using this
convenient and mild metalation condition, various CHdO, CdC
containing pyridine N-oxides were prepared (Table 1, entries
2-4, 7 and 12), which otherwise are not readily available via
traditional oxidation conditions.
Regioselective metalation of 2,5-dibromopyridine via metal-
bromine exchange has been studied extensively.17 Magnesiation
was reported to occur selectively at the C(5) position, using
bromine-magnesium based reactions.17g-k Selective metalation
could be achieved at the 2-position via lithiation under harsh
conditions,17c-e or iodine-magnesium exchange with the cor-
responding 5-bromo-2-iodopyridine.17j In light of the promising
results obtained in Table 1, we were prompted to explore the
selective magnesiation at the 2(or 6)-position of pyridine
N-oxides based on the strong inductive effect from N-oxide.
Substituted di- or tribromopyridine N-oxides were chosen as
the substrates and the results were outlined in Table 2. Our study
clearly indicated that the di- or tribromopyridine N-oxides can
be selectively magnesiated at the 2 (or 6)-position under mild
conditions. This has provided an alternative route to selectively
magnesiate the 2(or 6)-position of pyridine system.
Utilizing the aforementioned magnesiation condition to
functionalize the pyridine 2-position, we have successfully
completed the total synthesis of two naturally occurring 2,2′-
bipyridyl compounds, caerulomycins E and A (Scheme 1).18
Compound 2-bromo-6-methylpyridine N-oxide (1k) was first
magnesiated and transmetalated with ZnCl2 or Bu3SnCl. It was
then coupled with 2-bromopyridine in situ under Pd-mediated
Negishi or Stille conditions to yield key 2,2′-bipyridyl inter-
mediate 3 in 72% yield. It is noteworthy that this synthetic
approach also provides a general method to prepare mono
N-oxide of unsymmetrical 2,2′-bipyridyl compounds.
results showed that reaction proceeded rapidly and exclusively
with i-PrMgCl·LiCl (within 1-2 h). The optimal magnesiation
temperature was found to be between -40 and -60 °C, while
a higher temperature led to reaction of the Grignard reagent
with the oxide.9 Next a series of iodo- or bromopyridine
N-oxides were examined by using i-PrMgCl·LiCl at -40 °C
and the results are summarized in Table 1. In general, 2(or 6)-,
3- (or 5-), and 4-iodopyridine N-oxide derivatives can be
efficiently magnesiated (Table 1, entries 1-9). However,
corresponding metalation of 3(or 5)-, 4-bromopyridine N-oxides
with bromine-magnesium failed to give the desired products
(Table 1, entries 10 and 11). Instead, two side reactions were
observed: (a) the reaction of i-PrMgCl·LiCl with the oxides
leading to a dienal oxime as reported9 and (b) the deprotonation
of 2(or 6-)-hydrogen (e.g., 2j). As expected, 2(or 6)-bomopy-
ridine N-oxide derivatives were successfully magnesiated
through a bromine-magnesium exchange (Table 1 entries
12-17). Slightly better yields were obtained with 6-substituted-
2-bomopyridine N-oxides (Table 1 entries 15-17). Under this
magnesiation condition, good yields were also obtained for the
pyridine N-oxide system tethered with electrophilic functional
(16) For reviews, see: (a) Hiriyakkanavar, I.; Baron, O.; Wagner, A. J.;
Knochel, P. Chem. Commun. 2006, 583. (b) Hiriyakkanavar, I.; Baron, O.;
Wagner, A. J.; Knochel, P. Chem. Lett. 2005, 34, 1. (c) Knochel, P.; Dohle, W.;
Gommermann, N.; Kneisel, F. F.; Kopp, F.; Korn, T.; Sapountzis, I.; Vu, V. A.
Angew. Chem., Int. Ed. 2003, 42, 4302. (d) Rottla¨nder, M.; Boymond, L.;
Berillon, L.; Lepretre, A.; Varchi, G.; Avolio, S.; Laaziri, H.; Que´guiner, G.;
Ricci, A.; Cahiez, G.; Knochel, P. Chem. Eur. J. 2000, 6, 767. For some recent
papers, see: (e) Fleming, F. F.; Gudipati, S.; Vu, V. A.; Mycka, R. J.; Knochel,
P. Org. Lett. 2007, 9, 4507. (f) Kopp, F.; Knochel, P. Org. Lett. 2007, 9, 1639.
(g) Wang, X. J.; Sun, X. F.; Zhang, L.; Xu, Y. B.; Krishnamurthy, D.;
Senanayake, C. H. Org. Lett. 2006, 8, 305. (h) Wang, X.J.; Sun, X.F.; Zhang,
L.; Xu, Y. B.; Krishnamurthy, D.; Senanayake, C. H. Org. Lett. 2006, 8, 3141.
(i) Krasovskiy, A.; Straub, B. F.; Knochel, P. Angew. Chem., Int. Ed. 2006, 45,
159.
Nitration of 6-methyl-2,2-bipyridine N-oxide (3) gave 4
followed by nucleophilic substitution of sodium methoxide to
J. Org. Chem. Vol. 74, No. 2, 2009 941

yield 4-methoxy-2,2-bipyridine N-oxide (5). Treatment of 5 with
Ac2O, followed by hydrolysis led to (4-methoxy-2,2′-bipyridin-
6-yl)methanol (6). With the further modification of 6, Caeru-
lomycins E and A were synthesized with an overall yield of
46% and 40%, respectively. This represented a significant
improvement compared with those reported previously (caeru-
lomycins E: Que´guiner’s six-step synthesis from 2,2′-bipyridine,
an overall yield of 26%;18a caerulomycins A: Que´guiner’s
synthesis from 2,2′-bipyridine, 20% yield;18a Divekar’s two-
step synthesis from 4-methoxy-2,2′-bipyridine N-oxide, 8%
yield;18d De Souza’s four-step synthesis, 5% yield18c). In
addition, the reagents used in our synthesis are readily available
and corresponding procedures are very straightforward.
In conclusion, for the first time magnesiation of pyridine
N-oxides via an iodine or bromine-magnesium exchange was
achieved. This metalation provides a very useful tool to
functionalize the pyridine N-oxides without deoxygenation. This
methodology has enabled us to achieve (1) convenient prepara-
tions of a series of the N-oxides that are not readily obtained,
(2) regioselective magnesiation of di- or tribromopyridine
N-oxides at the 2(or 6)-position in the presence of 3(or
5)-bromine(s), and (3) efficient synthesis of a mono pyridine
N-oxide of an unsymmetrical 2,2′-bipyridyl compound, leading
to a facile total synthesis of Caerulomycins E and A. Further-
more, this magnesiation also extends the scope of Knochel’s
Grignard reagent preparation.
Experimental Section
General Procedure for Magnesiation of Iodo- or Bromo-
pyridine Pyridine N-Oxides and Reaction with Electrophile.
Under argon, a four-necked flask equipped with a magnetic stirrer
was charged with pyridine N-oxide (6 mmol) in 40 mL of THF.
The mixture was cooled to -60 to -40 °C, and i-PrMgCl·LiCl
(prepared and titrated according to the reported procedure,19 6.3
mmol) was added slowly with a syringe while the reaction
temperature was kept under -40 °C. The mixture was stirred at
-60 to -40 °C until starting material was consumed (monitored
by TLC). In the case of transmetalation (Table 1, entries 3, 4, 7,
12, 14, and Table 2, entry 4), a solution of CuI ·2LiCl in THF (6.3
mmol) was added with a syringe and the resulting mixture was
stirred at -60 to -40 °C for 20 min. The electrophile reagent (7
mmol) was then added and it was stirred under the same temperature
until starting material was fully consumed (monitored by TLC).
The reaction was quenched with 10% aqueous NH4Cl solution and
taken up with CH2Cl2. The organic layer was collected and
concentrated. The resulting crude material was purified by flash
chromatography to give the desired products. Note: When H2O was
used as an electrophile, the reaction was quenched directly.
(17) For selective lithiation of 2,5-dibromopyridine with n-BuLi, see: (a)
Parham, W. E.; Piccirlli, R. M. J. Org. Chem. 1977, 42, 257. (b) Bolm, C.;
Ewald, M.; Felder, M.; Schlingloff, G. Chem. Ber. 1992, 125, 1169. (c) Kondo,
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Enkelmann, V.; Baumgarten, M. J. Org. Chem. 2003, 68, 9907. For selective
lithiation of 2,5-dibromopyridine with TMSCH2Li, see: (f) Doudouh, A.;
Woltermann, C.; Gros, P. C. J. Org. Chem. 2007, 72, 4978. For magnesiation
of 2,5-dibromopyridine, see: (g) Tre´court, F.; Breton, G.; Bonnet, V.; Mongin,
F.; Marsais, F.; Que´guiner, G. Tetrahedron Lett. 1999, 40, 4339. (h) Tre´court,
F.; Breton, G.; Bonnet, V.; Mongin, F.; Marsais, F.; Que´guiner, G. Tetrahedron
2000, 56, 1349. (i) Iida, T.; Wada, T.; Tomimoto, K.; Mase, T. Tetrahedron
Lett. 2001, 42, 4841. (j) Song, J. J.; Yee, N. K.; Tan, Z.; Xu, J.; Kapadia, S. R.;
Senanayake, C. H. Org. Lett. 2004, 6, 4905. (k) Getmanenko, Y. A.; Twieg,
R. J. J. Org. Chem. 2008, 73, 830.
Acknowledgment. We gratefully acknowledge the Beijing
Key Subject Program and Dr. Yao Ma for revising this
manuscript as well as his helpful advice.
Supporting Information Available: Typical experimental
procedures and characterization data. This material is available
free of charge via the Internet at http://pubs.acs.org.
(18) (a) Tre´court, F.; Gervais, B.; Mongin, O.; Gel, C. L.; Mongin, F.;
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Ranganathan, S.; Singh, B. B.; Divekar, P. V. Can. J. Chem. 1969, 47, 165.
JO802172F
(19) (a) Krasovskiy, A.; Knochel, P. Angew. Chem., Int. Ed. 2004, 43, 3333.
(b) Krasovskiy, A.; Knochel, P. Synthesis 2006, 890.
942 J. Org. Chem. Vol. 74, No. 2, 2009