DifluoromethylenationDOI: 10.1002/ange.200604783

Stereoselective Difluoromethylenation Using Me3SiCF2SPh:Synthesis of Chiral 2,4-Disubstituted 3,3-Difluoropyrrolidines**Ya Li and Jinbo Hu*

As the most electronegative element, fluorine has attractedenormous attention recently in the fields of agricultural andmedicinal chemistry as well as in materials science.[1] Nowa-days, the efficient and selective incorporation of fluorineatom(s) or fluorine-containing moieties into organic mole-cules to modulate their biological properties has become aroutine and powerful strategy in drug design. Asymmetricfluorination and fluoroalkylation are two categories offascinating reactions in organofluorine chemistry, and enan-tioselective electrophilic fluorinations and enantioselectivenucleophilic monofluoromethylation represent the state-of-the-art achievements.[2] Currently, enantioselective trifluoro-methylation and difluoromethylation are still very challeng-ing topics with respect to stereoselectivity and generality,while highly diastereoselective trifluoromethylations anddifluoromethylations have been achieved by using suitablechiral auxiliaries.[2a,3, 4] In 2001 Prakash et al. reported anelegant diastereoselective nucleophilic trifluoromethylationof N-(tert-butylsulfinyl)imines using the Ruppert–Prakashreagent (TMSCF3),

[5] and recently we described highlydiastereoselective nucleophilic difluoromethylations andmonofluoromethylations using PhSO2CF2H and PhSO2CH2Fas the di- and monofluoromethylating agents, respectively.[4]

The pyrrolidine unit is ubiquitous in natural products, andrecently it was found that the 3,3-difluoropyrrolidine moietyplays very important roles in a variety of enzyme inhibitorssuch as coagulation factor Xa (or thrombin) inhibitors[6c] andcathepsin inhibitors,[6d] among others.[6e–g] It was rationalizedthat fluorine substitution on the pyrrolidine moiety candecrease the basicity of the amine functionality and inhibitthe enzymatic recognition processes and associated metabolicpathways, resulting in the enhanced biological activity andmetabolic stability of a drug candidate.[6] However, we are notaware of any reports of the efficient synthesis of chiral 2,4-disubstituted 3,3-difluoropyrrolidines. As part of our con-tinuing efforts in the development of efficient fluoroalkyla-tion methodologies, herein we report a highly diastereoselec-

tive difluoromethylenation method using [difluoro(phenyl-thio)methyl]trimethylsilane (1, TMSCF2SPh)

[7] as a difluoro-methylene radical anion equivalent. Using this appraoch, weeffectively synthesized chiral 2,4-disubstituted 3,3-difluoro-pyrrolidines 7 from N-(tert-butylsulfinyl)imines 2 following aselective nucleophilic addition/radical cyclization strategy(Scheme 1).

First, we carried out the diastereoselective nucleophilic(phenylthio)difluoromethylation of (R)-(tert-butylsulfinyl)-imines 2 with reagent 1. Compound 2a was used as a modelcompound to study the reaction, and the reaction conditionswere carefully tuned as shown in Table 1. We tried LiOAc,

CsF, and tetrabutylammonium triphenyldifluorosilicate(TBAT) as the Lewis base initiators for the reaction andfound that in all cases excellent diastereoselectivities (d.r.� 99:1) were observed and that the use of 0.3–0.5 equivalentsof TBAT in DMF solution gave the best yield of 3a (Table 1,entries 3 and 5).

Scheme 1. Use of TMSCF2SPh (1) as a difluoromethylene radical anionequivalent. TMS=Me3Si.

Table 1: Optimization of reaction conditions.

Entry Reaction conditions[a] d.r.[b] Yield [%][c]

1 LiOAc (1.1 equiv), DMF �99:1 302 CsF (1.1 equiv), DMF �99:1 673 TBAT (0.5 equiv), DMF �99:1 754 TBAT (0.5 equiv), THF �99:1 575 TBAT (0.3 equiv), DMF �99:1 716 TBAT (0.2 equiv), DMF �99:1 64

[a] For entries 1 and 2, the reaction mixture was maintained at�40 8C for2 h then at�20 8C for 4 h; for entries 3–6, the reaction was maintained at�40 8C for 1 h then at �20 8C for 4 h. [b] d.r.= (Rs,S)/(Rs,R), determinedby 19F NMR spectroscopy on a sample from the crude product mixture.[c] Yield of isolated product. DMF=N,N-dimethylformamide.

[*] Y. Li, Prof. Dr. J. HuKey Laboratory of Organofluorine ChemistryShanghai Institute of Organic ChemistryChinese Academy of Sciences354 Feng-Lin Road, Shanghai, 200032 (China)Fax: (+86)21-64166128E-mail: jinbohu@mail.sioc.ac.cn

[**] Support of our work by the National Natural Science Foundation ofChina (20502029), Shanghai Rising-Star Program (06A14063), andthe Chinese Academy of Sciences (Hundreds Talent Program) isgratefully acknowledged.

Supporting information for this article is available on the WWWunder http://www.angewandte.org or from the author.

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Eventually, we chose the reaction conditions listed underentry 3 (Table 1) as the standard conditions to study the scopeof the reaction between imines 2 and 1. The results aresummarized in Table 2. High diastereoselectivity was

observed in each case, and good yields were obtained withnon-enolizable imines (Table 2, entries 1–5 and 10) and withimines that bear only one a-hydrogen atom (entries 6–8).However, relatively lower yields (30–45%) were obtained inthe case of imine 2 i, which bears two a-hydrogen atoms(Table 2, entry 9). Careful TLC analysis revealed that imine2 i disappeared shortly after the reaction was performed andindicates a labile enolization of 2 i under such basic con-ditions. Note that products 3 are useful precursors for thepreparation of chiral a-difluoromethyl amines. For instance,(phenylthio)difluoromethylated sulfinamide 3d was treatedwith Bu3SnH/AIBN in toluene at 90 8C and the mixture wassubjected to acid-catalyzed alcoholysis with HCl/MeOH toafford a-difluoromethyl 2-naphthalenemethanamine 4 (in saltform) in 85% yield (Scheme 2). The specific rotation of 4 wasconsistent with that of the (S)-a-difluoromethyl 2-naphtha-lenemethanamine salt we reported earlier.[4a] The resultdemonstrates that the stereochemical outcome of the (phe-

nylthio)difluoromethylation reaction with imines 2 is orien-tated by a non-chelation-controlled addition mode.[4] Indeed,the present diastereoselective (phenylthio)difluoromethyla-tion of N-(tert-butylsulfinyl)imines 2 provides an alternative

approach for the preparation ofhomochiral a-difluoromethylamines, which we previously syn-thesized by using PhSO2CF2H.[4a]

We transformed the above-obtained sulfinamides 3 to the N-allylated products 5 in good yieldsby acid-catalyzed alcoholysis toremove the tBuS(O) group, fol-lowed by N-allylation with allylbromide. The results are summar-ized in Table 3. With the expect-ation that the F2C�S bond could becleaved homolytically under radicalconditions,[8] we carried out theintramolecular radical cyclizationreaction of 5 under thermal initia-tion in the presence of Bu3SnH anda catalytic amount of AIBN. Thecyclization reaction proceededsmoothly, and both trans products7 and cis products 7’ were obtainedin good yields, with 5-exo cycliza-tion being favored exclusively(Table 3). 19F NMR spectroscopicanalysis of the crude mixture indi-cated that the diastereoselectivity(7/7’) was up to 11:1 (Table 3,entry 5). The absolute configurationof the major trans product 7a(Table 3, entry 1) was confirmedby NOESY experiments (Scheme 3and Supporting Information) andwas consistent with our predictionbased on a Beckwith–Houk transi-

tion-state model.[9] As shown in Table 3, the radical cycliza-tion reaction gave good product yields and good diastereo-selectivity with aryl-substituted substrates (Table 3, entries 1–3). With a 2-furyl group, the yield of 7d was moderate and thediastereoselectivity dropped (Table 3, entry 4). For the alkyl-substituted substrates, a longer reaction time was requiredand afforded the cyclization products 7e and 7 f in reasonableyields and with high diastereoselectivity (Table 3, entries 5and 6). The present intramolecular cyclization reaction

Table 2: Stereoselective (phenylthio)difluoromethylation of sulfinylimines 2 with TMSCF2SPh.

Entry Sulfinylimine 2 Product 3 Yield[%][a]

d.r.[b]

1 75 �99:1

2 85 �98:2

3 89 �99:1

4 85 �98:2

5 72 �98:2

6 75 �99:1

7 74 �99:1

8 58 �99:1

930(45[c])

�99:1

10 71 �99:1

[a] Yields of isolated analytically pure material. [b] Diastereomeric ratios were determined by 19F NMRspectroscopy of the crude reaction mixture. [c] 1.0 equivalent of TBAT was used. Bn=benzyl.

Scheme 2. Preparation of a-difluoromethyl amine salt 4 from 3d.AIBN=azobis(isobutyronitrile).

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provides a new method for the synthesis of pyrrolidines thatcontain a midchain gem-difluoromethylene (CF2) moiety.

In summary, we have successfully developed a newsynthetic application of TMSCF2SPh as a difluoromethyleneradical anion synthon based on the selective ionic cleavage ofits F2C�Si bond and radical cleavage of its F2C�S bond.Nucleophilic (phenylthio)difluoromethylation of (R)-(N-tert-butylsulfinyl)imines with TMSCF2SPh affords the corre-sponding products in good yields and with high diastereose-lectivity (d.r.� 98:2). The obtained PhSCF2-containing sulfi-namides can be further transformed into chiral 2,4-trans-disubstituted 3,3-difluoropyrrolidines through an intramolec-ular radical cyclization methodology.

Experimental SectionTypical procedures for the stereoselec-tive (phenylthio)difluoromethylation ofsulfinylimines 2 with TMSCF2SPh (1):TBAT (702 mg, 1.3 mmol) was addedunder N2 atmosphere to a 30-mLSchlenk flask containing N-(tert-butyl-sulfinyl)aldimine (2a ; 548 mg,2.6 mmol) and PhSCF2TMS (734 mg,3.0 mmol) in DMF (10 mL) at �40 8C.The reaction mixture was stirred at thistemperature for 2 h, and then the tem-perature was raised to �20 8C and thereaction mixture was stirred for another4 h. Aqueous saturated NH4Cl solution(10 mL) was then added to the mixtureat this temperature, and the mixture wasextracted with EtOAc (25 mLE3). Thecombined organic phase was dried overMgSO4, and the volatile solvents wereremoved under reduced pressure. Thecrude product was further purified bysilica gel column chromatography withethyl acetate/petroleum ether (1:3 v/v)to give product 3a as a white solid(721 mg, 75% yield).

Typical procedure for preparation ofthe N-allylated products 5 : HCl/dioxane(4n ; 0.3 mL) was added under N2 atmos-phere into a 10-mL flask containing 3a(443 mg, 1.2 mmol) in anhydrous meth-anol (5 mL). The reaction mixture wasstirred at room temperature for 1 h, andthen the solvent was removed to give theintermediate product, which was used inthe next step without further purifica-tion. A mixture of the intermediateproduct and anhydrous K2CO3 (332 mg,2.4 mmol) in DMF (5 mL) was stirred atroom temperature until the intermedi-

ate product was consumed. Then H2O (10 mL) was added, and themixture was extracted with Et2O. The combined organic phase wasdried over MgSO4, and the solvent was removed to give the crudeproduct, which was further purified by silica gel column chromatog-raphy with ethyl acetate/petroleum ether (1:30 v/v) to give product 5aas an oil (286 mg, 78% yield).

Typical procedure for the intramolecular radical cyclizationreaction of N-allylated compounds 5 : Bu3SnH (0.38 mmol, 0.10 mL)and catalytic AIBN (2.0 mg) were added under N2 atmosphere to a10-mL Schlenk flask containing 5a (76 mg, 0.25 mmol) in toluene(2 mL) at 90 8C, and the reaction mixture was then stirred at thistemperature for 2 h. Then, another portion of AIBN (2.0 mg) wasadded and the reaction mixture was stirred for another 3 h. Aqueoussaturated KF solution (10 mL) was then added to the mixture at roomtemperature, and the solution mixture was extracted with Et2O(25 mLE3). The combined organic phase was dried over MgSO4, andthe volatile solvents were removed under reduced pressure. The crudeproduct was purified by silica gel column chromatography with ethylacetate/petroleum ether (1:5 v/v) to give product 7a as an oil (37 mg,75% yield).

Received: November 24, 2006Published online: February 27, 2007

.Keywords: enantioselectivity · fluoroalkylation · pyrrolidines ·radical reactions · synthetic methods

Table 3: Stereoselective synthesis of 2,4-substituted 3,3-difluoropyrrolidines 7.

Entry Product 5 Yield(5) [%][a]

Product 7 Yield(7) [%][a]

d.r.(7/7’)[b]

1 78 75 11:1

2 76 71 9:1

3 75 77 10:1

4 72 43 5:1

5 72 52 11:1

6 61 50 10:1

[a] Yield of isolated product. [b] Diastereomeric ratios were determined by 19F NMR spectroscopy of thecrude reaction mixture.

Scheme 3. Determination of configurations of 7a and 7a’ with NOESYexperiments.

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