Direct alkylation of pyridine 1-oxides

Abramovitch, R. A.; Smith, Elizabeth M.; Knaus, Edward E.; Saha, M.

doi:10.1021/jo00976a003

Cited by 39 publications

(11 citation statements)

References 7 publications

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“…The title compound was obtained in pure form as a white solid by recrystallization from acetone, mp 137 "C (Found: C, 62.0; H, 5.8; N, 4.7. C1,H17N0, requires C, 61.85; H, 5.9; N , 4 2,6-Diiodo-3,4dimethoxypyridine N-oxide 24d. Anhydrous 3,4-dimethoxypyridine N-oxide (I .25 g, 8.0 mmol) was added to a cold (-75 "C) solution of BuLi (26.5 mmol) in THF (120 cm3).…”

Section: -[ Hydroxy(2-methoxyphenyl)methyl]-34dimethoxypyridine N-oxi...mentioning

confidence: 99%

Metallation of pyridine N-oxides and application to synthesis

Mongin¹,

Rocca²,

Thomas‐Dit‐Dumont³

et al. 1995

J. Chem. Soc., Perkin Trans. 1

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Regio-and chemi-selective, directed ortho-lithiation of 2-, 2,5-or 3,4-substituted pyridine N-oxides has been achieved with diisopropylamide and butyllithium. Polysubstituted pyridine N-oxides, azaxanthone, and an isomer of orelline have been synthesized by such methods.Compared to the directed ortho-metallation of pyridine, little work on the lithiation of pyridine N-oxides has been reported apart from the pioneering studies of Abramovitch and his group between 1969 and 1972.2-6 In this they both developed the lithiation of pyridine N-oxide as well as various 3-, 4-and 3,4substituted compounds at low temperature, and proved, that in such compounds, the enhanced acidity of 2-H and the lithiumcomplexing effect of the oxygen lone pairs makes feasible under strongly basic conditions (treatment with lithium alkyls or lithium dialkylamides) proton abstraction ortho to nitrogen.This work has remained unexploited since these studies mainly because the low selectivity of this reaction often gave mixtures of 2-, 6and 2,6-functionalized products. Although this original work was later developed by Martin' using an in situ trap technique based on the compatibility between LTMP (lithium 2,2,6,6-tetramethylpiperidide) and such electrophiles as trimethylsilyl chloride or hexafluoroacetone, the problem of regioselectivity remained.Recently, since we developed an interest in preparing 2or 6-substituted pyridines or pyridine N-oxides for synthetic purposes, we have studied the metallation of pyridine N-oxides, particularly in respect of the 2/6-regioselectivity of such reactions.Two different regioselective pathways are investigated in this paper: the 6-lithiation of 2-substituted pyridine N-oxides 1-3 for which dimetallation cannot occur since the 2 position is blocked. and the 2-lithiation of 3-substituted pyridine N-oxides for which the substituent at C-3 can be an ortho-directing group. The latter example consists of the metallation of 3,4dimethoxypyridine N-oxide and some applications of this strategy are given with the synthesis of polyaromatic compounds. Results and discussion Metallation of 2-substituted pyridine N-oxidesLithiation of 2-N,N-diisopropylcarboxamidopyridine N-oxide 7 1 and 2-pivaloylaminopyridine N-oxides $ 2 and 3 with lithium diisopropylamide (LDA) in tetrahydrofuran (THF) at -75 "C (Scheme 1 ) occurred with total regioselectivity at the C-6 position. No metallation occurred at the C-3 position, although carboxamides and pivaloylamino groups are known to be ortho-directing groups under other conditions.' Reaction of t 2-( N,N-Diisopropylcarboxamido) pyridine N-oxide 1 was prepared from the corresponding pyridinecarboxamide in 70% yield by action of hydrogen peroxide in acetic acid at 80 "C for 12 h.8Pyridine N-oxides 2 and 3 were prepared respectively from 2aminopyridine and 5-methyl-2-aminopyridine in a two-step sequence: i, ClCOBu', NEt,, ether, room temp., 2 h; ii, H202, MeCO,H, 80 "C, 12 h. The overall yields were 65% for 2 and 73% for 3.

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Section: -[ Hydroxy(2-methoxyphenyl)methyl]-34dimethoxypyridine N-oxi...mentioning

confidence: 99%

Metallation of pyridine N-oxides and application to synthesis

Mongin¹,

Rocca²,

Thomas‐Dit‐Dumont³

et al. 1995

J. Chem. Soc., Perkin Trans. 1

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“…By using cyclohexanone as an electrophile, it was also possible to compare the alkylmagnesium reaction with butyllithium more directly. 10 Regioselective 2-substitution of pyridine N-oxide 1f was achieved with cyclohexanone to yield 38% of product 2h ( Table 2, entry 1), which is an improvement compared to the previously isolated 7% yield using n-BuLi. 10 Analogously 2i and 2j were isolated in improved yields of 32% and 36%, respectively ( Table 2, entries 2 and 3).…”

Section: Contents Lists Available At Sciencedirectmentioning

confidence: 88%

“…10 Regioselective 2-substitution of pyridine N-oxide 1f was achieved with cyclohexanone to yield 38% of product 2h ( Table 2, entry 1), which is an improvement compared to the previously isolated 7% yield using n-BuLi. 10 Analogously 2i and 2j were isolated in improved yields of 32% and 36%, respectively ( Table 2, entries 2 and 3). In comparison, using alkyllithiums, the yields were 0% and 21%, respectively, and resulted in alkylation on the methyl groups.…”

Section: Contents Lists Available At Sciencedirectmentioning

confidence: 88%

“…A selective monohalogenation was observed which stands in strong contrast to the reaction performed using alkyllithium, which is reported to give mainly dihalogenated products. 10 The 4-phenyl substituted pyridine N-oxide 1e showed a different reactivity when treated with i-PrMgCl at À78°C followed by trapping with benzaldehyde. The major product was the result of direct nucleophilic attack followed by an oxidation to yield 2-isopropyl-4-phenyl substituted pyridine N-oxide in 56% yield and the expected product 2g was obtained in 38% yield ( Table 1, entry 8).…”

Section: Contents Lists Available At Sciencedirectmentioning

confidence: 99%

“…In comparison, using alkyllithiums, the yields were 0% and 21%, respectively, and resulted in alkylation on the methyl groups. 10 Furthermore, the corresponding 3,5-dimethyl pyridine N-oxide 1d gave rise to the hydroxy-cyclohexyl substituted Noxide 2k in 81% yield ( Table 2, entry 4). Pyridine N-oxides 1i and 1k, with 2-methoxy-and 2-chloro substituents, respectively, gave rise to a complex reaction mixture when reacted in the same manner (Table 2, entries 5 and 8).…”

Section: Contents Lists Available At Sciencedirectmentioning

confidence: 99%

See 2 more Smart Citations

Selective synthesis of 2-substituted pyridine N-oxides via directed ortho-metallation using Grignard reagents

Andersson

Gustafsson²,

Olsson³

et al. 2008

Tetrahedron Letters

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Pyridine and Pyridine Derivatives

Scriven¹,

Toomey²,

Murugan³

2000

Kirk-Othmer Encyclopedia of Chemical Technology

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Scriven, Eric F. V., Toomey, Joseph E., Jr., and Murugan, Ramiah (Reilly Industries, Inc.). Commercial manufacture, industrial chemistry, and market uses of pyridine and pyridine compounds are reviewed. Pyridines often serve as intermediates for manufacture of products that are bioactive, such as medicinals, herbicides, insecticides, and fungicides. Significant end products for these market applications are identified. Important physical properties are also listed. Discussion of manufacture includes raw materials used, energy utilization, economics, toxicity of compounds, and safety factors. Vol. 20, pp. 641–679, 110 refs. to September 1994.

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Direct alkylation of pyridine 1-oxides

Cited by 39 publications

References 7 publications

Metallation of pyridine N-oxides and application to synthesis

Metallation of pyridine N-oxides and application to synthesis

Selective synthesis of 2-substituted pyridine N-oxides via directed ortho-metallation using Grignard reagents

Pyridine and Pyridine Derivatives

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