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Synlett 2009(11): 1733-1736  
DOI: 10.1055/s-0029-1217366
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Phosphine-Catalysed Cyclisation of β-Hydroxy-α,α-Difluoroynones

Marie Schuler, Angèle Monney, Véronique Gouverneur*
Chemistry Research Laboratory, 12 Mansfield Road, Oxford OX1 3TA, UK
Fax: +44(1865)275644; e-Mail: veronique.gouverneur@chem.ox.ac.uk;

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Publication History

Received 9 January 2009
Publication Date:
12 June 2009 (online)

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Abstract

2-Benzylidene-4,4-difluorodihydrofuran-3(2H)-ones were synthesised in 58-86% yield via phosphine-promoted cyclisation of β-hydroxy-α,α-difluoroynones. The benzylidene group was found to be a suitable masked carbonyl group, thereby allowing for the validation of a novel route to 3,3-difluoro-2-hydroxy-γ-lactols.

Key words

phosphine - fluorine - furanone - catalysis

Since the publication in the mid-sixties of pioneering reports, nucleophilic phosphine organocatalysis has led to the discovery of new methods for ynone-dienone isomerisation [¹] and for the construction of carbo- and ­heterocycles. [²] Reactions employing electron-deficient alkenes, allenes, or alkynes have proven particularly advantageous for heterocyclic synthesis inclusive of structurally diverse sulfur-containing motifs. [²] [³] This topic was reviewed by Roush in 2004, [4] and more recently by Tang [5] and by Toy. [6] Although much effort has been devoted to this area of research, the usefulness of phosphine organocatalysis has not been explored with reactions involving fluorinated reactants. As part of a program focused on the development of novel routes to fluorinated heterocycles, we recently disclosed the gold(I)-catalysed 6-endo-dig ring closure of β-hydroxy-α,α-difluoroynones. [7] This chemistry led to difluorinated dihydropyranones which are valuable precursors of pyranose carbohydrate analogues. In recognition of the importance of difluorinated furanones as potential precursors of gem-difluorinated furanoses and nucleoside analogues, [8] we reasoned that, under phosphine catalysis, we could redirect the ring closure of β-hydroxy-α,α-difluoroynones towards a 5-exo-dig reaction pathway. This process would deliver difluorinated furanones featuring an exocyclic alkene functionality that could be further manipulated (Scheme  [¹] ).

In this paper, we advance phosphine organocatalysis and document an operationally trivial protocol for the synthesis of 2-benzylidene-4,4-difluoro-furan-3(2H)-ones from readily available precursors. We also demonstrate that the benzylidene group of the cyclised products is a suitable masked carbonyl group, and we present a reaction sequence allowing for the conversion of a representative 2-benzylidene-4,4-difluoro-furan-3(2H)-one into the corresponding 3,3-difluoro-2-hydroxy-γ-lactol.

Scheme 1

To probe the feasibility and the scope of the proposed phosphine-catalysed ring closure, we synthesised a series of β-hydroxy-α,α-difluoroynones 1a-g featuring different substituents on the alkyne or on the group flanking the alcohol. [9] To access 1a-g, we used a Reformatsky reaction coupling the necessary aldehyde with chlorodifluorobut-3-yn-2-ones that were variously substituted on position 4. This well-documented chemistry delivered 1a-g isolated in yields ranging from 38-86%. [¹0] Silyl-deprotection of unpurified 1g in the presence of catalytic amount of sodium methoxide afforded the terminal ynone 1h in 35% overall yield. The β-hydroxy-α,α-difluoroynone 1i was made accessible reacting the corresponding Weinreb amide with propynylmagnesium bromide (Scheme  [²] ).

Scheme 2

With the β-hydroxy-α,α-difluoroynones 1a-i in hand, we undertook the organocatalysed 5-exo-dig ring-closure step (Table  [¹] ). Treatment of 1a with 1,3-bis(diphenylphosphino)propane (dppp, 10 mol%), AcOH (40 mol%) in toluene at 60 ˚C pleasingly led within 5 hours to the formation of the desired difluorinated furan-3-one 2a in 58% yield (entry 1). These reaction conditions are similar to the ones applied for the cyclisation of the corresponding nonfluorinated ynones indicating that the presence of the gem-difluorinated group is not detrimental. [¹¹] The reaction is not sensitive to the nature of the group flanking the alcohols. Various hydroxylated ynones derived from enolisable or nonenolisable aldehydes were found to cyclise efficiently with chemical yields up to 86% (entries 2-5). Ynone 1d derived from benzyloxyacet­aldehyde also underwent the programmed 5-exo-dig cycli­sation uneventfully delivering the desired difluorinated furanone 2d in 75% yield (entry 5). [¹²] Under our standard conditions, the ring closure of β-hydroxy-α,α-difluoroynone 1f with the propyl group capping the alkyne gave 2f in only 11% yield (entry 6). This reaction afforded 73% of the 1,3-dienone 3f (Scheme  [³] ). This result was expected since the alkynone-dienone isomerisation is a well-precedented internal hydrogen reorganisation process and has been extensively documented in the literature with a range of nonfluorinated ynones. [¹] The substrates which did not respond to cyclisation or isomerisation were the terminal and the methyl-substituted ynones 1h and 1i that both led to decomposition upon treatment with substoichiometric amounts of dppp and AcOH (entries 7 and 8).

Scheme 3

Table 1 5-Exo-dig Ring-Closure of β-Hydroxy-α,α-Difluoroynones 1a-i

Entry Starting material R¹ R² Product Yield (%)a Z/E b
1 1a Cy Ph 2a 58 98:2
2 1b Ph Ph 2b 62 95:5
3 1c PhCH2CH2 Ph 2c 81 94:6
4 1d BnOCH2 Ph 2d 75 92:8
5 1e 4-F3CC6H4 Ph 2e 86 98:2e
6 1f Ph n-Pr 2f 11c 98:2e
7 1h PhCH2CH2 H 2h -d
8 1i Ph Me 2i -d
a Isolated yields.
b Determined from ¹9F NMR of the crude reaction mixture.
c Major product is 3f (73%).
d Decomposition.
e Z/E ratio determined by ¹9F NMR after purification.

For all substrates that cyclised successfully, the Z-isomers were produced predominantly (Z/E ratio ranging from 92:8 to 98:2). The double-bond geometry was assigned unambiguously based on NOE experiments conducted on alcohols 4c and 4d, which were synthesised by reduction (L-Selectride, THF, -78 ˚C) of 2c and 2d, respectively. These NOE experiments revealed a syn relationship for the two stereogenic centres.

Figure 1

From a mechanistic standpoint, the cyclisation is likely to involve the formation of a zwitterionic phosphonium intermediate A which deprotonates the pronucleophile. Intramolecular addition of the resulting conjugate base to the vinyl-phosphonium salt gives the ylide B. The desired cyclised product is obtained after prototropic shift and elimination of dppp. For related organocatalytic reactions mediated by bisphosphines, it has been suggested that the second phosphine may function as a general base catalyst (Scheme  [4] ). [¹c]

Scheme 4

We next turned our attention on the manipulation of these novel 2-benzylidene-4,4-difluoro-dihydrofuran-3(2H)-ones with the view to access 3,3-difluorinated-2-hydroxy-γ-lactols. We identified the exocyclic benzylidene group as a possible masked carbonyl unit, the unmasking event being an oxidative cleavage that would release benzoic acid as the only side product. This study was carried out with the model compound 2c (Scheme  [5] ). Upon treatment with 2 equivalents of L-Selectride in THF at -78 ˚C for 6 hours, 2c was firstly reduced to the alcohol 4c in 74% yield. Only one stereoisomer was observed in the crude reaction mixture (dr >20:1) and its syn stereochemistry was assigned based on NOE analysis (Figure  [¹] ). Following protection of the newly formed secondary alcohol (TBDMSCl, imidazole, DMF, 0 ˚C to r.t., 24 h, 51%), the benzylidene group was successfully oxidatively cleaved with a catalytic amount of RuCl3˙H2O used in combination with 6 equivalents of NaIO4 in a solvent mixture of H2O-CCl4-MeCN. This reaction delivered lactone 6c in 68% yield. [¹³] Reduction of 6c with DIBAL-H (4 equiv in CH2Cl2, -78 ˚C, 1 h) afforded the lactol 7c as a mixture of anomers (ratio 1:3) in 65% overall yield. Alternative routes to structurally related gem-difluorinated lactols and their conversion into gem-difluorinated nucleosides analogues have been reported in great detail by Qing and co-workers. [8h,i]

Scheme 5

The unique reactivity of phosphines compared to amines has stimulated the development of numerous novel reactions over the past decade. Their nonbasic character is an attractive property providing compatibility with base-sensitive substrates. In this paper, we demonstrate that phosphine organocatalysis allows for the 5-exo-dig cyclisation of β-hydroxy-α,α-difluoroynones, a challenging class of substrates that did not respond well to 6-endo-dig ring closure under basic or acid conditions or using catalysts other than gold(I) catalysts. [7] The dppp-mediated 5-exo-dig ring closure described herein is an operationally trivial route to access unusual 2-arylidene-4,4-difluorodihydrofuran-3(2H)-ones variously substituted at C5. The feasibility and the clean stereochemical outcome of the cyclisation process as well as the successful production of lactol 7c are key results that suggest that this chemistry provides a solid basis for the development of a de novo asymmetric synthesis of gem-difluorinated carbohydrates and nucleosides analogues. This work is currently in progress in our laboratories.

Acknowledgment

We thank the European Community for funding through a Marie Curie Fellowship (MEIF-CT-2006-039270 for MS). We also acknowledge Dr. Barbara Odell for performing the NOE analyses on compounds 4c and 4d.

9

For additional details on the synthesis of β-hydroxy-α,α-difluoroynones, see the Electronic Supporting Information of ref. 7.

12

General Procedure for Cyclisation of 1c
To a solution of 1c (200 mg, 0.64 mmol, 1 equiv) in anhydrous toluene (64 mL) was added under argon AcOH (15 µL, 0.255 mmol, 40 mol%) followed by dppp (26.3 mg, 0.064 mmol, 10 mol%). The reaction mixture was stirred at 60 ˚C for 4 h. The crude mixture was concentrated in vacuo at r.t., and the resulting solution was directly purified by column chromatography on silica gel (hexane-Et2O, 80:20) to give the product as a yellow oil (120 mg, 0.38 mmol) in a 60% yield.



( Z )-2-Benzylidene-4,4-difluoro-5-(2-phenylethyl)-dihydrofuran-3 (2 H )-one (2c)
R f = 0.68 (hexane-EtOAc, 80:20). ¹H NMR (400 MHz, CDCl3): δ = 2.25 (q, J = 7.3 Hz, 2 H, CH 2CH), 2.91-3.04 (m, 2 H, CH2Ph), 4.44-4.55 (m, 1 H, CF2CH), 6.65 (s, 1 H, C=CHPh), 7.25-7.46 (m, 8 H, 8 × ArH), 7.79 (br d, J = 6.8 Hz, 2 H, 2 × ArH). ¹³C NMR (100 MHz, CDCl3): δ = 29.5 (d, J = 6.4 Hz, CH2), 30.8 (CH2), 79.7 (dd, J = 27.2, 24.0 Hz, CH), 112.7 (CH), 113.3 (dd, J = 268.8, 256.4 Hz, CF2), 126.6 (CH), 128.6 (CH), 128.8 (CH), 129.0 (CH), 130.0 (CH), 131.3 (CH), 132.5 (C), 140.0 (C), 144.1 (dd, J = 4.8, 3.2 Hz, C), 186.5 (t, J = 25.2 Hz, C). ¹9F NMR (377 MHz, CDCl3): δ = -125.17 (dd, J = 282.3, 14.9 Hz, 1 F), -120.62 (dd, J = 281.7, 12.1 Hz, 1 F). IR (CH2Cl2): ν = 3055, 1751, 1266, 1135, 738 cm-¹. HRMS (CI+): m/z calcd for C19H17F2O2 [M + H]+: 315.1197; found: 315.1209.

13

Procedure for the Synthesis of 6c
To a stirred solution of 5c (47.6 mg, 0.11 mmol, 1 equiv) in MeCN-CCl4-H2O (1.5:1:1, 1 mL) were added NaIO4 (141 mg, 0.66 mmol, 6 equiv) and RuCl3˙H2O (0.9 mg, 4.4 µmol, 4 mol%). After 30 min, the reaction mixture was quenched by addition of H2O, and it was extracted three times with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. Purification by column chromatography on silica gel (hexane-Et2O, 95:5 to 90:10) gave the product as a white solid (26.5 mg, 74 µmol) in a 68% yield. R f = 0.23 (hexane-Et2O, 95:5). ¹H NMR (400 MHz, CDCl3): δ = 0.14 and 0.17 (2 × s, 6 H), 0.92 (s, 9 H), 2.05-2.15 (m, 2 H), 2.70-2.91 (m, 2 H), 4.25-4.36 (m, 1 H), 4.48 (dd, J = 14.8, 9.4 Hz, 1 H), 7.16-7.22 (m, 3 H), 7.25-7.32 (m, 2 H). ¹³C NMR (126 MHz, CDCl3): δ = -4.8 (CH3), -5.1 (CH3), 18.5 (C), 25.5 (CH3), 28.8 (d, J = 5.2 Hz, CH2), 30.7 (CH2), 71.2 (dd, J = 19.5, 19.6 Hz, CH), 77.8 (dd, J = 25.3, 24.6 Hz, CH), 120.8 (dd, J = 254.0-254.1 Hz, CF2), 126.7 (CH), 128.7 (CH), 128.9 (CH), 139.9 (C), 169.3 (d, J = 17.1 Hz, C=O). ¹9F{¹H} NMR (377 MHz, CDCl3): δ = -131.30 (d, J = 232.0 Hz, 1 F), -116.62 (d, J = 232.0 Hz, 1 F). IR (CH2Cl2): ν = 2950, 2900, 2833, 1810, 1263, 1153, 910, 735 cm-¹. MS (CI+): m/z = 374.25 [M + NH4]+.

9

For additional details on the synthesis of β-hydroxy-α,α-difluoroynones, see the Electronic Supporting Information of ref. 7.

12

General Procedure for Cyclisation of 1c
To a solution of 1c (200 mg, 0.64 mmol, 1 equiv) in anhydrous toluene (64 mL) was added under argon AcOH (15 µL, 0.255 mmol, 40 mol%) followed by dppp (26.3 mg, 0.064 mmol, 10 mol%). The reaction mixture was stirred at 60 ˚C for 4 h. The crude mixture was concentrated in vacuo at r.t., and the resulting solution was directly purified by column chromatography on silica gel (hexane-Et2O, 80:20) to give the product as a yellow oil (120 mg, 0.38 mmol) in a 60% yield.



( Z )-2-Benzylidene-4,4-difluoro-5-(2-phenylethyl)-dihydrofuran-3 (2 H )-one (2c)
R f = 0.68 (hexane-EtOAc, 80:20). ¹H NMR (400 MHz, CDCl3): δ = 2.25 (q, J = 7.3 Hz, 2 H, CH 2CH), 2.91-3.04 (m, 2 H, CH2Ph), 4.44-4.55 (m, 1 H, CF2CH), 6.65 (s, 1 H, C=CHPh), 7.25-7.46 (m, 8 H, 8 × ArH), 7.79 (br d, J = 6.8 Hz, 2 H, 2 × ArH). ¹³C NMR (100 MHz, CDCl3): δ = 29.5 (d, J = 6.4 Hz, CH2), 30.8 (CH2), 79.7 (dd, J = 27.2, 24.0 Hz, CH), 112.7 (CH), 113.3 (dd, J = 268.8, 256.4 Hz, CF2), 126.6 (CH), 128.6 (CH), 128.8 (CH), 129.0 (CH), 130.0 (CH), 131.3 (CH), 132.5 (C), 140.0 (C), 144.1 (dd, J = 4.8, 3.2 Hz, C), 186.5 (t, J = 25.2 Hz, C). ¹9F NMR (377 MHz, CDCl3): δ = -125.17 (dd, J = 282.3, 14.9 Hz, 1 F), -120.62 (dd, J = 281.7, 12.1 Hz, 1 F). IR (CH2Cl2): ν = 3055, 1751, 1266, 1135, 738 cm-¹. HRMS (CI+): m/z calcd for C19H17F2O2 [M + H]+: 315.1197; found: 315.1209.

13

Procedure for the Synthesis of 6c
To a stirred solution of 5c (47.6 mg, 0.11 mmol, 1 equiv) in MeCN-CCl4-H2O (1.5:1:1, 1 mL) were added NaIO4 (141 mg, 0.66 mmol, 6 equiv) and RuCl3˙H2O (0.9 mg, 4.4 µmol, 4 mol%). After 30 min, the reaction mixture was quenched by addition of H2O, and it was extracted three times with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. Purification by column chromatography on silica gel (hexane-Et2O, 95:5 to 90:10) gave the product as a white solid (26.5 mg, 74 µmol) in a 68% yield. R f = 0.23 (hexane-Et2O, 95:5). ¹H NMR (400 MHz, CDCl3): δ = 0.14 and 0.17 (2 × s, 6 H), 0.92 (s, 9 H), 2.05-2.15 (m, 2 H), 2.70-2.91 (m, 2 H), 4.25-4.36 (m, 1 H), 4.48 (dd, J = 14.8, 9.4 Hz, 1 H), 7.16-7.22 (m, 3 H), 7.25-7.32 (m, 2 H). ¹³C NMR (126 MHz, CDCl3): δ = -4.8 (CH3), -5.1 (CH3), 18.5 (C), 25.5 (CH3), 28.8 (d, J = 5.2 Hz, CH2), 30.7 (CH2), 71.2 (dd, J = 19.5, 19.6 Hz, CH), 77.8 (dd, J = 25.3, 24.6 Hz, CH), 120.8 (dd, J = 254.0-254.1 Hz, CF2), 126.7 (CH), 128.7 (CH), 128.9 (CH), 139.9 (C), 169.3 (d, J = 17.1 Hz, C=O). ¹9F{¹H} NMR (377 MHz, CDCl3): δ = -131.30 (d, J = 232.0 Hz, 1 F), -116.62 (d, J = 232.0 Hz, 1 F). IR (CH2Cl2): ν = 2950, 2900, 2833, 1810, 1263, 1153, 910, 735 cm-¹. MS (CI+): m/z = 374.25 [M + NH4]+.

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Scheme 1

Scheme 2

Scheme 3

Figure 1

Scheme 4

Scheme 5