Synthesis of fluorinated δ-lactams via cycloisomerization of gem-difluoropropargyl amides

• Satoru Arimitsu and
• Gerald B. Hammond

Beilstein J. Org. Chem. 2010, 6, No. 48, doi:10.3762/bjoc.6.48

• Satoru Arimitsu Gerald B. Hammond Department of Chemistry, Kyoto University, Kyoto, Japan Department of Chemistry, University of Louisville, Louisville, Kentucky 40292, United States 10.3762/bjoc.6.48 Abstract gem-Difluoro-1,7-enyne amides are suitable building blocks for the synthesis of

• difluorodihydropyridinones via a ring-closing metathesis reaction, and of 4,4-difluoro-3-oxoisoquinolines through a ring-closing metathesis–enyne metathesis tandem reaction. These products, in turn, undergo a Diels–Alder reaction to yield heterotricyclic systems in moderate to good yields. Keywords: bicyclic lactams

• -difluoromethylene moiety has been reported to improve their biological activities. For example, a gem-difluoro-γ-lactam can inhibit γ-lactamase, which is responsible for bacterial resistance to γ-lactam antibiotics [2][3][4]. Additionally, α,α-difluoro lactams are precursors of some biologically active compounds [5

9,10-Dioxa-1,2-diaza-anthracene derivatives from tetrafluoropyridazine

• Graham Pattison,
• Graham Sandford,
• Dmitrii S. Yufit,
• Judith A. K. Howard,
• John A. Christopher and
• David D. Miller

Beilstein J. Org. Chem. 2010, 6, No. 45, doi:10.3762/bjoc.6.45

• ): −86.2 (1F, dd, 5JFF = 31.2 Hz, 4JFF = 23.7 Hz, F-6), −94.5 (1F, dd, 5JFF = 31.2 Hz, 3JFF = 23.7 Hz, F-3), −140.4 (1F, dd, 3JFF = 23.7 Hz, 4JFF = 23.7 Hz, F-4); MS (ES+) m/z: 227 ([MH]+, 100%). 3,6-Difluoro-4,5-diphenoxypyridazine (8) Using the procedure described above, phenol (0.32 g, 3.45 mmol

• ), sodium hydride (0.138 g, 3.45 mmol, 60% dispersion in mineral oil), tetrafluoropyridazine (0.25 g, 1.64 mmol) and THF (20 mL) gave 3,6-difluoro-4,5-diphenoxypyridazine (8) (0.29 g, 59%) as a white solid; mp 123–124 °C; Anal. Calcd for C16H10F2N2O2: C, 64.0; H, 3.4; N, 9.3%. Found: C, 63.7; H, 3.5; N, 9.2

• , C-3); 19F NMR (658 MHz, CDCl3 δF): −88.2 (s); MS (ES+) m/z: 301 ([MH]+, 100%). Synthesis of 3,4-difluoro-9,10-dioxa-1,2-diaza-anthracene (5) Catechol (0.80 g, 7.2 mmol) was dissolved in THF (20 mL) at 0 °C under an argon atmosphere with stirring and added to sodium hydride (0.35 g, 14.5 mmol, 60

The C–F bond as a conformational tool in organic and biological chemistry

• Luke Hunter

Beilstein J. Org. Chem. 2010, 6, No. 38, doi:10.3762/bjoc.6.38

• , Figure 1a) there is an energetic penalty associated with the conformation in which the two C–F bonds are aligned parallel [6][7]. Molecules containing 1,3-syn fluorine substituents will therefore prefer to twist in order to avoid parallel 1,3-C–F dipoles. An alternative explanation for the 1,3-difluoro

• , which is perhaps a surprising result since the fluorine atoms might reasonably be expected to repel each other. What effect overrides the difluoro repulsion and stabilises the gauche conformer? There is a vacant low-energy σ* antibonding orbital associated with each C–F bond (Figure 1c). In the gauche

• difluoro gauche effect is overridden in this case) [24][26]. Dihydroquinidine (26, Figure 5) is a highly active anti-malarial alkaloid. It has conformational degrees of freedom about the C9–C4′ and C8–C9 bonds, and some information about the bioactive conformation of 26 can be obtained from the fluorinated

Three step synthesis of single diastereoisomers of the vicinal trifluoro motif

• Vincent A. Brunet,
• Alexandra M. Z. Slawin and
• David O'Hagan

Beilstein J. Org. Chem. 2009, 5, No. 61, doi:10.3762/bjoc.5.61

• be both regio- and stereo-selective [18][19]. When the reaction was carried out at 0 °C the resultant difluoro alcohol 10 was obtained in 36% yield, whereas the yield improved as the temperature was lowered (47% at −35 °C and 56% at −60 °C). Epoxide ring opening was stereospecific, and the (2S,3S,4S

• )-difluoro alcohol 10 was obtained as the major diastereoisomer in a 97:3 ratio. The third fluorine atom was inserted in a smooth reaction by treatment of 10 again with Deoxo-Fluor® to generate (2S,3R,4S)-11. The sequence illustrated in Scheme 4 validated the three step fluorination protocol for this

• diastereoisomeric series. Reaction of α,β-epoxy alcohol 7b with Deoxo-Fluor® also proceeded smoothly generating fluoro epoxide (2S,3S,4R)-9b in 95% yield and as a single stereoisomer. However when 9b was treated with HF/pyridine [19][20] there was no evidence that the expected difluoro alcohol 12b had formed

Novel banana-discotic hybrid architectures

• Hari Krishna Bisoyi,
• H. T. Srinivasa and
• Sandeep Kumar

Beilstein J. Org. Chem. 2009, 5, No. 52, doi:10.3762/bjoc.5.52

• , the bent core unit will disrupt it owing to its rigidity and high volume fraction compared to the other alkyl chains surrounding the triphenylene disc which otherwise provide space filling effect for columnar mesomorphism. The difluoro compound 8b, has a lower melting point than its hydrocarbon parent

Understanding the mechanism of Pd-catalyzed allylic substitution of the cyclic difluorinated carbonates

• Jun Xu,
• Xiao-Long Qiu and
• Feng-Ling Qing

Beilstein J. Org. Chem. 2008, 4, No. 18, doi:10.3762/bjoc.4.18

• , Shanghai 201620, China 10.3762/bjoc.4.18 Abstract We present a mechanistic investigation of Pd-catalyzed allylic substitution of cyclic gem-difluorinated carbonates 1 and 4, previously employed in the synthesis of 3',3'-difluoro-2'-hydroxymethyl-4',5'-unsaturated carbocyclic nucleosides in 17 steps. The

• prepare potential bioactive fluorinated nucleosides, our group recently described the stereoselective synthesis of 3',3'-difluoro-4',5'-unsaturated OTCs 2–3 and 5 [11]. The whole synthesis highlighted the stereoselective Reformatskii-Claisen rearrangement, ring-closing metathesis (RCM), and Pd-catalyzed

The vicinal difluoro motif: The synthesis and conformation of erythro- and threo- diastereoisomers of 1,2-difluorodiphenylethanes, 2,3-difluorosuccinic acids and their derivatives

• David O'Hagan,
• Henry S. Rzepa,
• Martin Schüler and
• Alexandra M. Z. Slawin

Beilstein J. Org. Chem. 2006, 2, No. 19, doi:10.1186/1860-5397-2-19

• - diastereoisomers of 2,3-difluorosuccinates. Results A synthetic route to 2,3-difluorosuccinates has been developed through erythro- and threo- 1,2-difluoro-1,2-diphenylethane which involved the oxidation of the aryl rings to generate the corresponding 2,3-difluorosuccinic acids. Ester and amide derivatives of the

• erythro- and threo- 2,3-difluorosuccinic acids were then prepared. The solid and solution state conformation of these compounds was assessed by X-ray crystallography and NMR. Ab initio calculations were also carried out to model the conformation of erythro- and threo- 1,2-difluoro-1,2-diphenylethane as

• genuine vicinal difluoro motif-CHF-CHF- and only 12 crystal structures of this motif are deposited in the Cambridge Structure Data Base. The relatively rare presence of this motif may partly be attributed to the difficulty of their selective synthesis. It remains a synthetic challenge to prepare vicinal