Furopyridines. XI. 13C NMR Spectra of 2‐ or 3‐Substituted Furo[2,3‐b]‐, Furo[3,2‐b]‐, Furo[2,3‐c]‐ and Furo[3,2‐c]pyridine

Shiotani, Shunsaku; Morita, Hiroyuki

doi:10.1002/jhet.5570280601

Cited by 17 publications

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References 20 publications

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“…A solution of furopyridine 1a-d [2][3][4][5] (1.0 mmol) in dry ether (ca. 3 ml) was added to liquid ammonia (10 ml), and sodium metal (3.0 or 1.8 mmol) was then added to the solution, and the mixture was stirred for 30 minutes.…”

Section: General Procedures For Birch Reduction Of 1a-dmentioning

confidence: 99%

Furopyridines. XXXI. Birch reduction of furopyridines

Yamaguchi

Hamade

Yokoyama

et al. 2002

Journal of Heterocyclic Chem

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Birch reduction of four furopyridines 1a-d effected the characteristic cleavage of the furan ring, giving ethnylpyridinols 2a-d, vinylpyridinols 3b,d, and ethylpyridinols 4a-d, and the reduction of the furan ring, giving dihydrofuropyridine 5c,d. J. Heterocyclic Chem., 39, 335 (2002).Furopyridines have a fused structure containing both a π-excess furan ring and a π-poor pyridine ring, and so, being interested in their chemical properties, we have studied the synthesis and reactions of furopyridine derivatives [1][2][3][4][5]. In this paper we report the Birch reduction of four furopyridines 1a-d.Birch reduction has been adopted for the reduction of aromatic systems, including some hetero-aromatic systems [6]. The reduction of some π-excess furans undergo a 1,4-reduction giving the corresponding 2,5-dihydrofurans. The reduction of π-poor pyridines undergo a 1,4-reduction, giving 1,4-dihydropyridines, or a cleavage of the pyridine ring, causing re-cyclization to give cyclohexenones.Four furopyridines 1a-d were subjected to Birch reduction using 3.3 equivalents of sodium metal in liquid ammonia [6], and the results are summarized in Table. As shown in Scheme 1, in the Birch reduction of furopyridines 1a-d, very interestingly, all resulted in the specific cleavage of the furan ring giving a mixture of ethynylpyridinol 2, vinylpyridinol 3, and ethylpyridinol 4. In the case of 1c and 1d, the reduction, giving dihydrofuropyridine 5c,d was also observed.Birch reduction of furo [2,3-b]pyridine (1a)[2] using 3.3 equivalents of sodium metal quantitatively gave two products, 3-ethynyl-2-pyridinol (2a) and 3-ethyl-2-pyridinol (4a) in the ratio of 1:2. Birch reduction of furo[3,2-b]pyridine (1d)[5] using 3.3 equivalents of sodium metal gave three products (in 88% total yield), 2-ethynyl-3-pyridinol (2d), 2-vinyl-3-pyridinol (3d), and 2-ethyl-3-pyridinol (4d) in the ratio of 1:2:3. Use of 1.8 equivalents of sodium metal gave four products (in 67% total yield), 2d, 3d, 4d, and 2,3-dihydro[3,2-b]pyridine (5d) in the ratio of 3:4:4:1. These results suggested that the vinyl and the dihydro derivatives are the intermediates for further reduction. Birch reduction of furo [2,3-c]pyridine (1b)[3] using 3.3 equivalents of sodium metal gave three products (in 63% total yield), 4-ethynyl-3-pyridinol (2b), 4-vinyl-3-pyridinol (3b), and 4-ethyl-3-pyridinol (4b) in the ratio of 1:2:5. Birch reduction of furo[3,2-c]pyridine (1c)[4] using 3.3 equivalents of sodium metal also gave three products (in 50% total yield), 3-ethynyl-4-pyridinol (2c), 3-ethyl-4-pyridinol (4c), and 2,3-dihydrofuro[3,2-c]pyridine (5c) in the ratio of 1:6:2.In all cases, the Birch reduction of furopyridine yielded ethynylpyridiols 2 and ethylpyridinols 4. The former ethynylpyridinols 2 were not reduction products (valenceisomerized compounds), and the latter ethylpyridinols 4 might be doubly reduced compounds. As already reported, a similar cleavage giving the correspoinding ethynylpyridinols was observed in treating 3-bromofuropyridines with alkyl lithium [7]. This sugg...

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Section: General Procedures For Birch Reduction Of 1a-dmentioning

confidence: 99%

Furopyridines. XXXI. Birch reduction of furopyridines

Yamaguchi

Hamade

Yokoyama

et al. 2002

Journal of Heterocyclic Chem

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“…N - (2( R )-Hydroxy-1( S )-indanyl)-2( R )-phenylmethyl-4( S )-hydroxy-5-(1-(4-(2-(6-methylfuro[3 ,2- c ]pyridyl)methyl)-2( S )- N ‘ -( tert -butylcarboxamido)piperazinyl))pentanamide (31). The preparation of 2-formyl-6-methylfuro[3,2- c ]pyridine followed in analogous fashion from the synthesis of 2-formylfuro[3,2- c ]pyridine, using β-(3-furyl)methacrylic acid in place of β-(3-furyl)acrylic acid. Starting from 2-formyl-6-methylfuro[3,2- c ]pyridine and amine 2 and following the procedure outlined in method A, compound 31 was prepared as a white solid in 78% yield: mp 101−110 °C; TLC (MeOH:CHCl 3 saturated with NH 3 :CH 2 Cl 2 , 10:30:60) R f = 0.36; 1 H NMR (400 MHz, CDCl 3 ) δ 1.36 (s, 9H), 1.49−1.58 (m, 1H), 1.91−2.01 (m, 1H), 2.25 (br s, 1H), 2.43−2.50 (m, 2H), 2.52−2.62 (m, 4H), 2.64 (s, 3H), 2.70−3.03 (m, 7H), 3.09 (br s, 1H), 3.61 (d, J = 14.1 Hz, 1H), 3.66 (d, J = 14.1 Hz, 1H), 3.78−3.86 (m, 1H), 4.14 (br s, 1H), 4.28 (dd, J = 4.9, 3.9 Hz, 1H), 5.26 (dd, J = 8.4, and 4.9 Hz, 1H), 6.43 (d, J = 8.6 Hz, 1H), 6.62 (s, 1H), 7.05−7.29 (m, 10H), 7.92 (br s,1H), 8.70 (s, 1H); HRMS (FAB-POSI; M + 1) calcd 668.3811, found 688.3803.…”

Section: Methodsmentioning

confidence: 99%

Identification of MK-944a: A Second Clinical Candidate from the Hydroxylaminepentanamide Isostere Series of HIV Protease Inhibitors

et al. 2000

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Recent results from human clinical trials have established the critical role of HIV protease inhibitors in the treatment of acquired immune-deficiency syndrome (AIDS). However, the emergence of viral resistance, demanding treatment protocols, and adverse side effects have exposed the urgent need for a second generation of HIV protease inhibitors. The continued exploration of our hydroxylaminepentanamide (HAPA) transition-state isostere series of HIV protease inhibitors, which initially resulted in the identification of Crixivan (indinavir sulfate, MK-639, L-735,524), has now yielded MK-944a (L-756,423). This compound is potent, is selective, and competitively inhibits HIV-1 PR with a K(i) value of 0.049 nM. It stops the spread of the HIV(IIIb)-infected MT4 lymphoid cells at 25.0-50.0 nM, even in the presence of alpha(1) acid glycoprotein, human serum albumin, normal human serum, or fetal bovine serum. MK-944a has a longer half-life in several animal models (rats, dogs, and monkeys) than indinavir sulfate and is currently in advanced human clinical trials.

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“…Assigned 13 C NMR shifts (DMSO- d 6 ) of the quinuclidin-2-ene (Q2−Q8) and benzofuran (C2−C7a) carbons of the 5- and 7-substituted quinuclidin-2-ene derivatives. The 13 C NMR spectra were assigned by using standard shift theory, comparisons with selected benzofuran derivatives, and 1 H− 13 C heteronuclear NMR correlation experiments (2 pages) . Ordering information is given on any current masthead page.…”

Section: Supporting Information Availablementioning

confidence: 99%

3-(2-Benzofuranyl)quinuclidin-2-ene Derivatives: Novel Muscarinic Antagonists

et al. 1996

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A series of 26 derivatives of the novel muscarinic antagonist 3-(2-benzofuranyl)quinuclidin-2-ene (1) has been synthesized and evaluated for muscarinic and antimuscarinic properties. The affinity of the compounds was determined by competition experiments in homogenates of cerebral cortex, heart, parotid gland, and urinary bladder from guinea pigs using (-)-[3H]-3-quinuclidinyl benzilate as the radioligand, and the antimuscarinic-potency was determined in a functional assay on isolated guinea pig urinary bladder using carbachol as the agonist. The 5-fluorobenzofuranyl derivative was slightly more potent than 1. The 7-bromo-substituted 8 displayed a 14-fold tissue selectivity ratio for muscarinic receptors in the cortex versus the parotid gland. Comparative molecular field analysis and quantitative structure-activity relationship models were developed for this series of substituted benzofuranyl derivatives.

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Furopyridines. XI. ¹³C NMR Spectra of 2‐ or 3‐Substituted Furo[2,3‐b]‐, Furo[3,2‐b]‐, Furo[2,3‐c]‐ and Furo[3,2‐c]pyridine

Cited by 17 publications

References 20 publications

Furopyridines. XXXI. Birch reduction of furopyridines

Furopyridines. XXXI. Birch reduction of furopyridines

Identification of MK-944a: A Second Clinical Candidate from the Hydroxylaminepentanamide Isostere Series of HIV Protease Inhibitors

3-(2-Benzofuranyl)quinuclidin-2-ene Derivatives: Novel Muscarinic Antagonists

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