Tert-Butanesulfinamides As Nitrogen Nucleophiles in Carbon-Nitrogen

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tert-Butanesulfinamides as Nitrogen Nucleophiles in Carbon-Nitrogen Bond Forming Reactions Johana Ramirez Hernandez, Fabrice Chemla, Franck Ferreira, Olivier Jackowski, Julie Oble, Alejandro Perez-Luna, Giovanni Poli

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Johana Ramirez Hernandez, Fabrice Chemla, Franck Ferreira, Olivier Jackowski, Julie Oble, et al.. tert-Butanesulfinamides as Nitrogen Nucleophiles in Carbon-Nitrogen Bond Forming Reactions. CHIMIA, Schweizerische Chemische Gesellschaft, 2016, 70 (1), pp.84-92. 10.2533/chimia.2016.84. hal-01292458

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doi:10.2533/chimia.2016.84 Chimia 70 (2016) 84–92 © Swiss Chemical Society tert-Butanesulfinamides as Nitrogen Nucleophiles in Carbon–Nitrogen Bond Forming Reactions

Johana Ramirez Hernandez, Fabrice Chemla, Franck Ferreira, Olivier Jackowski, Julie Oble, Alejandro Perez-Luna*, and Giovanni Poli

Abstract: The use of tert-butanesulfinamides as nitrogen nucleophiles in carbon–nitrogen bond forming reactions is reviewed. This field has grown in the shadow of the general interest in N-tert-butanesulfinyl imines for asymmetric synthesis and occupies now an important place in its own right in the chemistry of the chiral amine reagent tert-butanesulfinamide. This article provides an overview of the area and emphasizes recent contributions wherein the tert-butanesulfinamides act as chiral auxiliaries or perform as nitrogen donors in metal-catalyzed amination reactions. Keywords: Amination · tert-Butanesulfinamide · Chiral nucleophiles

1. Introduction In this context, the performance of charged sulfur atom means that the tert-bu- tert-butanesulfinamides as nitrogen nu- tanesulfinyl group attenuates considerably Chiral amine reagent tert-butanesulfin- cleophiles raises increasing interest. On the nucleophilicity of the nitrogen atom of amide (1) has received massive attention the one hand it represents a possibility to tert-butanesulfinamides. Leaving aside the over the last decade and has found applica- elaborate further the α-branched amines above-mentioned condensation reactions tions in an ever-increasing number of re- produced from additions to N-tert-bu- with aldehydes and ketones that have been search areas.[1] In the field of asymmetric tanesulfinyl imines (Scheme 1, A). On the reviewed previously[1] and will not be dis- synthesis, it is now a well-established tool other hand, a number of recent reports have cussed here, reactions with carbon electro- for the preparation of chiral non-racemic evidenced that tert-butanesulfinamides can philes are essentially of two types: (i) those amines. Rapid access to both enantiomeric perform as chiral nitrogen nucleophiles in that rely on the intermediate formation of a forms of tert-butanesulfinamide, high lev- nucleophilic amination reactions produc- main-group metal amide and (ii) those, less els of stereodiscrimination and easy re- ing a new stereocenter, and that stereoin- common, that involve a transition-metal moval of the sulfinyl moiety under mild duction is possible with excellent levels catalyzed process. acidic conditions constitute major advan- of diastereoselectivity (Scheme 1, B). The tages to the use of the tert-butanesulfinyl purpose of this article is to showcase the group as chiral auxiliary on nitrogen. possibilities offered by the use of tert-bu- 2. Reactions Involving Metallated Asymmetric synthesis of enantiopure chi- tanesulfinamides as nitrogen nucleophiles N-tert-Butanesulfinamides as ral amines using tert-butanesulfinamide in asymmetric synthesis and to emphasize Nucleophiles usually follows a well-established pattern the recent contributions wherein the sulfi- that entails condensation with a carbonyl nyl moiety acts as chiral auxiliary. Main-group anions of tert-butanesul- derivative and a subsequent reaction at the The combination of the steric bulk of finamide (1) and its N-substituted conge- electrophilic carbon atom of the N-sulfinyl the tert-butyl moiety and the electron- ners react readily with an array of carbon imine thereby produced (Scheme 1, A).[1] withdrawing effect of the positively electrophiles. Their good resistance to

A: tert-Butanesulﬁnyl imines as chiral electrophiles: functionalization by chiral C–Nbond formation induction O O O O O – S 2 S + E S S R1 N tBu R HN tBu E N tBu H N tBu 2 * * R1 1 2 1 2 1 R R R R B: tert-Butanesulﬁnamidesaschiral nucleophiles : chiral induction R1 R2 O *Correspondence: Dr. A. Perez-Luna O R S N tBu Sorbonne Universités R S LG stereoselective UPMC Univ Paris 06, UMR CNRS 8232 N tBu * C–Nbond formation Institut Parisien de Chimie Moléculaire H R1 R2 F-75005, Paris, France E-mail: [email protected] Scheme 1. Uses of tert-butanesulfinamides as nucleophiles in asymmetric synthesis. The French connecTion CHIMIA 2016, 70, No. 1/2 85

racemization makes them privileged inter- cally pure form. For most of the reported With stronger bases such as NaH- mediates to carry out N-functionalization examples, the cyclization precursors are MDS[14] or LiHMDS[15] in DMF, ring- without losing the chiral information on α-branched sulfinamides obtained from closure has been obtained at much lower the sulfur atom. Strategies for N-alkylation N-tert-butanesulfinyl imines and, with temperatures (–40 °C) as for the formation and N-acylation have been developed as the notable exception of aziridine forma- of 4. well as aza-Michael reactions. tion, the carbon undergoing substitution The preparation of diazaspiro[3.3] is primary. Heterocyclizations leading to heptane 5[16] by intramolecular alkylation 2.1 N-Alkylation of tert-Butanesul- the formation of rings ranging from 3 to triggered with tBuOK in THF, evidences finamides 7 members have been accomplished and that four-membered heterocyclization is N-alkylationoftert-butanesulfinamides a rather large variety of reagents and con- also possible with tert-butanesulfinamide can be achieved by deprotonation and elec- ditions have been described (Scheme 2). nucleophiles, but such reactions are not trophilic trapping of the corresponding A possible reason for this is the absence common. By contrast, five-membered ring metal amide with alkyl halides. In the case of a truly general cyclization method and formation by displacement of a halide leav- of tert-butanesulfinamide (1), the process the fact that, quite often, ring closure for ing group is far more usual and has been is complicated by competitive dialkylation a given substrate-type or cyclisation mode implemented in several ways (Scheme 2). and, even if treatment with KOH can be only proceeds under precise experimental It has been accomplished either at 50 °C a solution to obtain N-monoalkylation,[2] conditions (base, solvent, temperature, by treatment with KOH in H O/THF[17] or 2 reductive amination approaches are gen- …). Thus, the correct choice of these con- tBuOK in iPrOH,[13] or at room tempera- erally preferred.[3] The strategy is thus ditions is a key element to achieve the de- ture in THF using LiHMDS[18] (see the most useful for the functionalization of N- sired transformation. formation of 6), KHMDS,[19] or a combi- substituted tert-butanesulfinamides. Not Cyclization of β-chloro N-tert-butane- nation of NaH and a crown ether additive only are these products widely accessible sulfinamides to aziridines is a favorable (15-Crown-5).[20] As illustrated with 7, the through nucleophilic addition or reduction reaction that has been achieved at high latter conditions are tolerant of functional- of tert-butanesulfinyl imines, but also in- temperature by treatment with KOH in ized substrates. It is also noteworthy that troduction of a second nitrogen substituent H O/THF,[11] as illustrated with the prepa- efficient pyrrolidine formation has been 2 is not possible by reductive amination. ration of 2 (Scheme 2), K CO in acetone, described by intramolecular displace- 2 3 Metallation of N-alkyl tert-butanesul- as shown with 3,[12] or tBuOK in iPrOH.[13] ment of mesylate[21] or tosylate[22] leaving finamides can be carried out conveniently using mainstream strong bases such as KH, NaH, LiHMDS, KHMDS or nBuLi. The O O tBu S Conditions O tBu most used solvents are THF or DMF and S S N tBu R2 NH often the reactions are performed at tem- R2 N 1 n peratures higher than –30 °C. Regioselec- R X n tive N-alkylation is generally obtained, but enantiopure enantiopure the competitive S-alkylation might ham- O tBu O tBu O tBu S per the process in the case of substrates O tBu S S S N where the sulfinyl nitrogen is sterically O N N N H Me Cl Me hindered.[4] Me MeO Cl Ph Me Me OBoc N 2.1.1 Intermolecular N-Alkylation Me Ts Reactions 2:73% (X=Cl) 3:88% (X=Cl) 4:85% (X=Cl) 5:84% (X=Br) Conditions: Conditions: Conditions: Conditions: Reports on intermolecular N-alkylation KOH (3.0 equiv) K2CO3 (3.0 equiv) NaHMDS (1.0 equiv) tBuOK (1.4 equiv) reactions of metallated tert-butanesulfin- THF:H2O(1:1) acetone DMF THF amides with non-activated alkyl halides 50 °C,24h reﬂux, 24 h –40°C, 20 min 0°C, 20 min other than methyl iodide[5] are rare.[6] By O tBu O tBu S O tBu O tBu contrast, allylic and propargylic halides are S S S N well-suited electrophiles that permit inter- N N N Ph MOMO MOMO molecular allylation and propargylation N reactions that are particularly important PMBO Boc from an applicative point of view. First 6:98% (X=Cl) 7:96% (X=Cl) 8:75% (X=OMs) 9:78% (X=Cl) they open up possibilities for subsequent Conditions: Conditions: Conditions: Conditions: rapid construction of nitrogen heterocycles LiHMDS (1.5 equiv) NaH (3.0 equiv) tBuOK (2.0 equiv) NaH (4.0 equiv) THF 15-crown-5 (4.0 equiv) THF,rt, 1h 15-crown-5 (3.0 equiv) which are useful both for target-orient- 23 °C,1h THF,20°C, 6h THF,20°C, 6h ed[7,8] and diversity-oriented synthesis.[9] O tBu Second, N-allyl tert-butanesulfinamides S tBu O have been recently uncovered as valuable N O tBu O tBu S S S N chiral ligands in the context of transition- N Ph N Me metal enantioselective catalysis.[10] Me MeO Me 2.1.2 Intramolecular N-Alkylation N OMe Ts Reactions 10:76% (X=Cl) 11:99% (X=Cl) 12:72% (X=Br) 13:85% (X=OTs) Base-mediated intramolecular N-alkyl- Conditions: Conditions: Conditions: Conditions: ation of tert-butanesulfinamides is a syn- NaH (1.0 equiv) NaH (2.5 equiv) KHMDS (1.3 equiv) NaH (2.1 equiv) thetically useful reaction that has received DMF DMSO THF THF,20°C, 20 h significant attention because it gives 0to25°C, 6h 80 °C,2h 0to25°C, 1h straightforward access to chiral substitut- Scheme 2. Representative examples of heterocyclization by intramolecular N-alkylation of tert- ed nitrogen heterocycles in enantiomeri- butanesulfinamides with halides and related leaving groups. 86 CHIMIA 2016, 70, No. 1/2 The French connecTion

groups in the presence of either tBuOK, as O O M R2 for the formation of 8, or NaH. 1 O S R M M S In the case of six-membered ring con- tBu N N tBu LG S N tBu struction, the use of NaH as base has been R2 R2 (B) (A) R1 * * privileged (Scheme 2). Again, it has been (LG =Cl) R1 LG LG used in combination with 15-crown-5, in THF at room temperature, to prepare func- tionalized piperidines like 9.[23] However, O tBu in solvents with higher polarity, similar cy- S N clizations have been accomplished without the crown ether additive. For instance, the R1 **R2 formation of tetrahydroisoquinolines such Organometallic nucleophiles used for (A) Carbenoids used for aza-Darzens-type condensations (B) as 10 has been achieved in DMF at room O SiMe temperature,[24] and 3-substituted piperi- R1 MgX 3 BrZn dines like 11 have been prepared in DMSO Li P(OEt)2 BrZn Br at 80 °C.[25] I Cl 1 Finally, even though ring closure to af- R CeCl2 14 15 16 ford seven-membered rings is not always Li I Li CO2Et Li H Na SO2Ph [18b] straightforward, azepane formation has I been reported by intramolecular displace- Br X Br PhO2SF2C K ment of a bromide following deprotonation 17 X=I: 18 20 21 X=Cl: 19 with KHMDS,[13] as in the case of 12, as well as by displacement of a tosylate leav- Scheme 3. Aziridine formation by one-pot tandem nucleophilic addition/intramolecular alkylation [26] ing group using NaH (formation of 13). reactions. A notable aspect of these intramolecular N-alkylation reactions is that it is possible to embed them in one-pot tandem pot tandem reactions have been imple- out without racemization and the acylated sequences that entail the addition of an mented to access nitrogen heterocycles derivatives have been obtained in enantio- organometallic reagent on a N-tert-bu- other than aziridines are scarce. They con- merically pure form if enantiopure tert-butanesulfinyl imine and the subsequent ring cern the asymmetric synthesis of 2-sub- tanesulfinamides were used. The ureas and closure of the metal amide produced. Such stituted pyrrolidines and piperidines by some of the amides prepared in this way transformations have been achieved by in- reductive cyclization of γ- or δ-chlorinated have emerged as valuable organocatalysts troducing a suitable leaving group for the N-tert-butanesulfinyl ketimines on reac- for asymmetric catalysis.[42a,44,45] alkylation step (usually a halide) either on tion with LiBHEt (Scheme 4).[17,18b] As N-acylation of N-alkyl tert-butanesul- 3 the imine undergoing the condensation or shown with the preparation of 24 from 22 finamides has been achieved in a similar in the nucleophile used. and 25 from 23, the reduction step was way. There are some intermolecular exam- Aziridine synthesis has received con- carried out at –78 °C, while cyclization by ples[46] but these reactions have been mostly siderable attention in this context and has intramolecular alkylation required heating implemented in the context of heterocycle been accomplished following the two pos- to room temperature. Note that extension construction by intramolecular processes. sible approaches (Scheme 3). On the one of this methodology to prepare lager rings Cyclizations of tert-butanesulfinamides hand (A), α-chloro N-tert-butanesulfinyl (azepanes and azocines) was not success- having tethered esters[47] or amides,[48] in- imines have been reported to provide ful. cluding lactams,[49] have been used for the the corresponding aziridines upon reac- preparation of β-lactams and pyrrolidones. tion with organomagnesium[11a,27] and or- 2.2 N-Acylation of tert-Butanesul- It has also been possible to obtain the N- ganocerium[28] reagents, as well as with finamides acylation of the metal amides arising from KCF SO Ph.[29] On the other hand (B), N-Acylation of tert-butanesulfin- the addition of an organometallic reagent 2 2 aza-Darzens-type condensations between amides has also been achieved via the cor- to N-tert-butanesulfinyl imines and this has carbenoid reagents and N-tert-butane- responding metal anions. Lithium or po- paved the way for the elaboration of one- sulfinyl imines have been disclosed with tassium anions of tert-butanesulfinamide pot tandem synthetic strategies (Scheme a rather large array of carbanions. These (1) have been reported to react with car- 5). For instance, 5-methylene 2-pyrrol- include: lithiated halomethylphospho- boxylic anhydrides[41] and esters[42,43] to idones such as 27 have been prepared by nates like 14,[30] zincated propargylic and provide the corresponding N-tert-butane- a sequence involving the Barbier-type al- allylic bromides 15[31] and 16,[32] a lithi- sulfinyl amides, and with isocyanates[44] lylation of 26 followed by intramolecular ated (chloroethyl)oxazoline,[33] lithiated and 1,1’-carbonyldiimidazole[45] to give reaction with the pending ester.[47b,c] An- bromoesters such as 17,[34] lithiated halo- N-tert-butanesulfinyl ureas. Even though other representative example is the forma- methanes 18 and 19,[35] the sodium anions it has been an issue in certain cases,[41] tion of 3,5-disubstituted pyrrolidone 29 of bromoform,[36] chloroform[14] and halo these reactions have been usually carried by a process initiated by the addition of methylsulfones (i.e. 20),[37] and the lithium or potassium anions of dihalo methanes (21).[38] It is also important to mention that Scheme 4. Pyrrolidine condensation of sulfur ylides[39] as well as O LiBHEt3 O tBu and piperidine for- S tellurium ylides[40] with N-tert-butanesul- S (1.5 equiv.) mation by reductive N tBu N finyl imines is a related process that has Ph cyclization of γ- or Cl THF δ-chlorinated N-tert- also been used to develop some efficient Ph n=1,2 –78°C, 1h n=1,2 stereoselective synthetic approaches to N- butanesulfinyl keti- then rt mines. tert-butanesulfinyl aziriridines. n=1,22 n=1,24:92%, 99:01 dr Examples in which similar truly one- n=2,23 n=2,25:94%, 99:01 dr The French connecTion CHIMIA 2016, 70, No. 1/2 87

a Grignard reagent to N-sulfinyl imine 28 Scheme 5. that involves a subsequent cyclization on Me Representative exam- [48] Br OMe ples of heterocycliza- an amide. tBu O O tion by intramolecular Lastly, it is also worthy to note that O S S O β-lactam 31, an intermediate used for the N tBu (2 equiv.) N N-acylation of tert- butanesulfinamides. semi-synthesis of taxol, has been prepared Zn, LiCl Me from 30 by an intramolecular peptide cou- OMe MeO OMe DMF,rt, 8h MeO pling reaction (Scheme 5).[50] 26 27 : >78%, 99.7:0.3 dr

2.3 Intramolecular aza-Michael Me Me Ph MgCl O O tBu Reactions (5 equiv.) N tBu Me N S tert-Butanesulfinamides participate N S O Me O CH2Cl2/Et2O1:3 readily as nitrogen nucleophiles in base- S –78°Cto–20 °C O mediated intramolecular aza-Michael O Ph reactions and the chirality of the sulfinyl 28 29:86%, 91:09 dr moiety has been successfully exploited to develop diastereoselective procedures for the asymmetric synthesis of five- and six- N Cl Me I membered nitrogen heterocycles. O (1.5 equiv.) O S Treatment of tert-butanesulfinamide S O tBu NH O Et N(1.5 equiv.) tBu 32, that has a tethered α-β-unsaturated ke- 3 N Ph OH CH CN, reﬂux, 6h tone, with a sub-stoichiometric amount of OBoc 3 Ph OBoc base afforded a mixture of diastereomeric 30 31:45% pyrrolidines 33a and 33b (Scheme 6).[51] It was shown that the process was reversible and that the stereoselectivity varied Scheme 6. O Me O tBu O tBu Asymmetric synthesis with the reaction conditions. With tBuOK O Base S S (0.3 equiv.) of pyrrolidines by at room temperature, formation of the S N N HN tBu + intramolecular aza- THF, T O O thermodynamic product 33a was favored Michael additions Me Me and a 33a/33b = 85:15 ratio was obtained. of tert-butanesulfin- 32 33a 33b Conversely, at –40 °C using KHMDS, amides on tethered 33b was produced as major product in a tBuOK, rt, 30 min: 33a +33b: 74%, 85:15 dr α-β-unsaturated reversed 33a/33b = 15:85 ratio. Related KHMDS, –40°C, 40 min: 33a +33b: 64%, 15:85 dr ketones. cyclizations with α-branched sulfinamides were also achieved. In the case of 34 hav- O Me O tBu O tBu O tBuOK S S ing an iPr substituent, the stereochemical (0.3 equiv.) S N N outcome was governed by the sulfinyl HN tBu R + R THF, T O O group: the thermodynamic product 35a R Me Me was obtained as major product at room 34:R=iPr 35a:R=iPr 35b:R=iPr temperature, while the kinetic product 35b 36:R=Ph 37a:R=Ph 37b:R=Ph was favored at –40 °C. By contrast, in the case of 36 with a Ph substituent, product rt, 30 min: 35a +35b: 93%, 86:14 dr 37a was formed exclusively, regardless of 37a +37b: 96%, >99:01 dr the reaction temperature. –40°C, 60 min: 35a +35b: 87%, 21:79 dr Inthepresenceofbase,α-β-unsaturated 37a +37b: 88%, >99:01 dr esters can also undergo intramolecular aza-Michael additions with tethered tert- butanesulfinamides to give five-membered Scheme 7. [51] O OtBu O tBu O tBu ring closures (Scheme 7). Similarly to O tBuOK S S Asymmetric synthesis (0.3 equiv.) the case of α-β-unsaturated ketones, the S N N of pyrrolidines by HN tBu addition is reversible and the sense of ste- THF, T O O diastereoselective intramolecular aza- reoinduction varies with the reaction tem- OtBu + OtBu perature. Thus, at –40 °C, the cyclization Michael additions of substrate 38 leads to the kinetic product 38 39a 39b of tert-butanesulfinamides on tethered 39b in an excellent 39a/39b = 06:94 ratio, rt: 39a +39b: 90%, 57:43 dr α-β-unsaturated while at room temperature, 39a is formed –40°C: 39a +39b: 92%, 06:94 dr esters. as major product, albeit with very low diastereomeric excess. Cyclization on ester Michael-acceptors major product in a 41a/41b = 80:20 ratio. addition irreversible and thus precludes has proved most useful in the construction Product 41a could be readily converted equilibration. The model proposed to ac- of substituted isoindolines (Scheme 8).[52] into 41b by equilibration in the presence count for the kinetic stereocontrol during As shown for substrate 40, a first set of of TBAF, thereby indicating that 41b was the cyclization step involves two competi- conditions involving treatment with TBAF the thermodynamic product and 41a the ki- tive chair-like transition states wherein the at room temperature allowed the forma- netic one. It was suggested by the authors negatively charged sulfinyl oxygen inter- tion of product 41b in good yield and ex- that the reaction proceeds under kinetic acts with the electrophilic carbon of the es- cellent stereoselectivity. If DBU was used control with DBU because its lower basic- ter group. M1 is favored over M2 because as base, formation of 41a was obtained as ity makes the protonation step following the tert-butyl group occupies a pseudo- 88 CHIMIA 2016, 70, No. 1/2 The French connecTion

equatorial position and not a pseudo-axial Scheme 8. Isoindoline one (Scheme 8). TBAF formation by diastere- This method has also been used to pre- oselective cyclization pare 2,3-disubstituted isoindolines from tBu of tert-butanesulfin- O tBu O tBu amides on tethered α-substituted N-tert-butanesulfinamides O S EtO S S O base α-β-unsaturated (Scheme 9).[52] It has been found that the NH N N CO Et CO Et esters. stereochemical behavior of the cycliza- THF 2 2 tion depends on the relative configuration 0°Ctort between the α-carbon and the stereogenic sulfur atom. In the case of substrates having 40 41a 41b the same relative configuration as 42, a ste- (kinetic) (thermodynamic) reodivergent process was observed and the TBAF (1.1 equiv.): 41a +41b: 75%, <05:95 dr choice of appropriate reaction conditions DBU (2.0 equiv.): 41a +41b: 45%, >80:20 dr made it possible to access, in good yields and excellent stereoselectivity, the cor- tBu tBu – + – responding 2,3-disubstituted isoindolines N O – O + S OEt N S δ+ – either as trans isomers (43a – kinetic con- δ+ O O trol) or cis isomers (43b – thermodynamic OEt control). By contrast, for substrates having M1 M2 the same relative configuration as 44, the cis isomer 45 was favored under both thermodynamic and kinetic control and was Scheme 9. thus obtained under all of the reaction con- tBu O tBu O tBu Asymmetric synthesis ditions. It is also worthy of mention, that in EtO S S of 2,3-disubstituted O S O CO2Et CO2Et N N the latter case, stereoselective isoindoline α NH base isoindolines by information was obtained directly from the + tramolecular aza- THF parent N-tert-butanesulfinyl imines by a Michael reaction. tandem sequence involving nucleophilic addition and cyclization through intra- 42 43a 43b molecular aza-Michael reaction.[53] The (kinetic) (thermodynamic) preparation of 47 from 46 illustrates well this sequence. TBAF: 43a +43b: 84%, <05:95 dr DBU: Formation of six-membered rings by 43a +43b: 58%, >95:05 dr base-mediated intramolecular aza-Michael tBu O tBu addition of tert-butanesulfinamides has al- EtO S O S O CO2Et so been reported and it has been used for NH N α TBAF or DBU Cl3C the asymmetric synthesis of 2-substituted Cl3C and 2,3-disubstituted piperidines (Scheme THF 10).[51] Cyclization of 48 occurred most efficiently in the presence of tBuOK at 44 45: >95:05 dr room temperature and yielded a mixture (kinetic /thermodynamic) of diastereomeric piperidines 49a and 49b tBu in 49a/49b = 88:12 ratio. By contrast with CF3TMS (2.0 equiv) O tBu O S EtO S the above-described five-membered ring O (nBu4N,SiF2Ph3) CO2Et N N closure leading to pyrrolidines 33a/33b, (2.0 equiv) F3C no variation of the stereoselectivity was THF observed upon modification of the reaction –55°Ctort conditions (temperature, base or solvent). 46 47: 94%, 99:01 dr Such was not the case for α-branched substrates, since reactions at room temperature gave very high selectivity (but moderate yields), while reactions at –40 °C led to Scheme 10. moderate stereoselectivity (in good yields). O tBu Asymmetric synthe- S O tBu O tBu Taking advantage of the reversibility of the tBuOK S S sis of piperidines by HN (0.3 equiv.) intramolecular aza- process, an optimized procedure combin- Me N + Me N ing high stereoselectivity and good yields O THF,rt Michael reaction. O O could eventually be obtained by adding the Me base at –40 °C and then letting the reaction 48 49a 49b temperature rise to room temperature. The 49a +49b: 78%, 88:12 dr synthetic value of this method is well evidenced with the cyclization of 50 to obtain O tBu S tBuOK O tBu 51 that has been used in natural product S [51] HN Me (0.3 equiv.) synthesis. Me N Me Piperidine formation is also readily O THF achieved by intramolecular aza-Michael –40°Cthen rt O reaction of tert-butanesulfinamides with Me 50 51: 61%, >99:01 dr tethered acrylates and occurs with excellent The French connecTion CHIMIA 2016, 70, No. 1/2 89

levels of stereoinduction.[51] This approach CO tBu 2 NaH has been very recently used to develop an tBu O CO tBu CO tBu CO tBu S (1.0 equiv.) 2 2 2 asymmetric synthesis of quinolizidine 54, tBu O tBu O tBu O NH THF,rt S CO tBu S CO tBu S CO tBu which was used for natural product synthe- 2 ++2 2 [54] N N N sis (Scheme 11). The approach involved 89% 2S 2S 2R as the first step the cyclization of diacrylate (72:24:4 dr) 52 in the presence of NaH that induced a CO2tBu 52 cis-53a trans-53a 53b desymmetrization process wherein two (63% isolated) (22% isolated) stereocenters were created. The intramolecular aza-Michael reaction afforded a 1) HCl, Dioxane 1) HCl, Dioxane 2) K CO 2) K CO mixture of diastereomers in which isomers 2 3 2 3 85% 85% having a 2S configuration predominated as the result of the chiral induction exerted CO2tBu CO2tBu by the tert-butanesulfinyl group. Products cis-53a and trans-53a, isolated in 63% N N CO tBu CO2tBu and 22% yields respectively, could then be 2 both engaged in a second intramolecular 54 54 aza-Michael addition that provided quinolizidine 54 in enantiomerically pure form. Transtition state models : Thus, because of the C2-symmetry of 54, tBu tBu the lack of stereocontrol of the relative S S O O H configuration of the C(2) and C(6) substit- CH2CO2tBu O Na N O Na N uents in the first step was not a problem. tBuO tBuO The authors rationalized the remarkable H CH2CO2tBu chiral induction achieved for the desym- M3 M4 metrization step on kinetic bases. It was suggested that the cyclization takes place trans-53a through a rigid chair-like transition state cis-53a involving a chelate between the sodium Scheme 11. Asymmetric synthesis of 54. amide, the sulfoxide and the ester carbonyl. The nitrogen nucleophile attacks the Si face of the acrylate to avoid steric interac- were formed in good yields and excel- states (M5 versus M6) wherein the sulfi- tions with the bulky tert-butyl group. This lent diastereoselectivity.[57] To account for nyl group and the free hydroxyethyl group induction mode operates regardless of the the observed stereoinduction, the authors are hydrogen-bonded. Cyclization through position occupied by the C(6) substituent proposed a kinetic-based model involving transition state model M5 was proposed to that can be either equatorial (favored) as in cyclization via two competitive transition be favored because non-bonding interac- M3 that gives cis-53a or axial as in M4 that gives trans-53a. Scheme 12. tBu O tBu Representative ex- PPh3 (1.2 equiv.) S S amples of Mitsunobu- O NH DEAD (1.2 equiv.) N 3. Mitsunobu Cyclizations of tert- type heterocyclization OH iPr Butanesulfinamides THF,rt, 24 h reactions. O iPr In the context of heterocyclization O OPMB OPMB reactions, another important feature of 55 56:73% N-alkyl tert-butanesulfinamides is that tBu they can be used as nucleophiles for Mit- O tBu S PPh3 (1.2 equiv.) S sunobu-type intramolecular alkylations O NH Ph DIAD (1.2 equiv.) N (Scheme 12). Typical Mitsunobu condi- Me OH tions (PPh and diethylazodicarboxylate 2 Me 3 THF,rt, 15 h (DEAD) or diisopropylazodicarboxylate Ph HO (DIAD)) are well suited to achieve pyrro- OH lidine ring closure. This reactivity was first 57 58:75%, >98:02 dr evidenced serendipitously with the unex- O H pected cyclization of 55 to 56[55] and has CH2Ph CH2Ph later provided synthetic solutions in target + H H O tBu Me S oriented-synthesis for cases in which other Ph3PO – + – N vs N Me cyclization conditions were not applicable Ph3PO O S or failed.[56] Interestingly, this chemistry H O tBu has been used to develop a very elegant M5 M6 access to stereodefined 2,2,3-trisubstituted pyrrolidines through a highly diastereose- O tBu O tBu lective Mitsunobu cyclization governed by S nBu3P=CHCN S the chiral tert-butanesulfinyl group. Start- NH (1.5 equiv.) N EtO2C EtO2C ing from diols such as 57, differentiation OH Toluene of the diastereotopic hydroxyethyl groups 110°C, 16 h was observed, and pyrrolidines like 58 59 60:70% 90 CHIMIA 2016, 70, No. 1/2 The French connecTion

tions between the tert-butyl and the C(2) substituents are avoided. Pd(OAc)2 (10 mol%) O Heterocyclization of tert-butanesulfin- rac-BINAP (20 mol%) S tBu N Ph2P O Br Cs2CO3 (2.0 equiv.) amides using the classical Mitsunobu con- H Ph2P S + ditions to give nitrogen heterocycles other tBu NH2 N O Toluene N O 120 °C,5d than pyrrolidines is less favorable and rac-BINAP Ph has only been reported for very specific Ph 1 61:84% substrates.[58] In order to circumvent this limitation, the use of cyanomethylenetri- Pd (dba) (2 mol%) butylphosphorane, a reagent that performs 2 3 tBuXPhos (5 mol%) tBu2P NO2 better for more demanding cyclizations, O NO2 NaOH (2.4 equiv.) O iPr iPr + has been considered. α-Substituted azeti- S S tBu NH2 Toluene/H2O95:05 tBu N Cl H dines, pyrrolidines and piperidines such as 90 °C,20h iPr 60 have been prepared with this method 1 62:92% tBuXPhos that requires nevertheless rather harsh reaction conditions (toluene, 110 °C).[59] Scheme 13. Representative examples of Pd(0)-catalyzed N-arylation of tert-butanesulfinamides.

4. Transition Metal-catalyzed system was used to obtain tetrahydroquin- nation reactions was envisaged at a quite Amination Reactions with tert- oline formation by intramolecular cross early stage as a route to chiral allylic Butanesulfinamides as Nitrogen coupling of a secondary tert-butanesulfin- amines but met with only limited success. Donors amide with a tethered aryl bromide, but in N-allylation of the lithium anion of 1 with this case the tert-butanesulfinyl group was racemic cyclic allylic carbonates in the The potential of tert-butanesulfin- presence of Pd(PPh ) was reported to be concomitantly removed (likely after cycli- 3 4 amides as nitrogen donors in metal-cata- zation).[63] low yielding and moderately stereoselec- lyzed amination reactions has only started A second system that has proved tive.[65] to be investigated very recently but it has more efficient for the N-arylation of tert- This reaction has been recently rein- already been demonstrated that they can butanesulfinamide (1) involves Pd (dba) vestigated by us using Pd(OAc) /diphe- 2 3 2 be suitable partners for N-arylation and N- as palladium source, tBuXPhos as ligand nylphosphino-ethane (dppe) as catalytic heteroarylation reactions, for N-allylation and NaOH as base.[64] In this case, cross system in order to gain insight on the in- reactions, including transformations where coupling has been achieved in toluene at fluence of N-substitution.[43] Unlike metal- they act as chiral inductors, and for hy- 90 °C, provided that a small amount of wa- lated tert-butanesulfinamide 1, anions of droamination reactions. ter was added to the reaction medium. Ar- N-benzyl tert-butanesulfinamide and N- ylbromides could be used as electrophiles, acetyl tert-butanesulfinamide (64) were 4.1 N-Arylation and N-Heteroary- but also arylchlorides, as shown with the found to react readily with allyl acetate. In lation of tert-Butanesulfinamides preparation of 62. Importantly, for both of the presence of BSA (N,O-bis(trimethyl) The prospect to carry out N-(hetero) the catalytic systems disclosed, no racemi- acetamide) and a catalytic amount of arylation of tert-butanesulfinamides has a zation was noted. AcOK, the use of a strong base could be two-fold interest. On the one hand, it of- avoided and N-allylation of 1 to afford 63 fers a convenient solution for the synthesis 4.2 Allylic Amination Reactions was achieved in reasonable yield, despite of N-(hetero)aryl tert-butanesulfinamides with tert-Butanesulfinamides competitive diallylation (Scheme 14). in enantiomerically pure form, which is The use of tert-butanesulfinamide (1) It was further shown that N-acyl tert- otherwise difficult to achieve. On the other as partner in Pd(0)-catalyzed allylic ami- butanesulfinamides undergo N-allylation hand, the ease of deprotection of the tert- butanesulfinyl group makes tert-butanesulfinamide (in racemic form) an interest- ing ammonia surrogate in carbon–nitrogen Pd(OAc)2 (5 mol%) bond forming cross-coupling reactions.[60] dppe (7,5 mol%) N-(hetero)arylation of tert-butanesul- BSA (1.1 equiv.) O AcOK (10 mol%) O finamide (1) was first reported under cop- + OAc S S tBu N per catalysis.[61] However, only the cross tBu NH2 THF 70 °C,16h H coupling with 2-bromopyridine was de- 1 63:56% scribed and, in spite of >90% conversion, no isolated yield nor characterization data O Pd(OAc) (5 mol%) O were given. This method has not been de- 2 S dppe (7,5 mol%) S veloped further. tBu NH + Ph OCO2Me tBu N Ph THF More general methods have been dis- O Me 70 °C,16h O Me closed with palladium catalysts (Scheme 64 13). As illustrated with the preparation 65:81%, E/Z >98:02 of 61, the system obtained by combin- OCO Me O 2 Pd(OAc)2 (5 mol%) O ing Pd(OAc) and rac-BINAP, catalyzed, dppe (7,5 mol%) 2 S S in the presence of Cs CO in toluene at tBu NH tBu N 2 3 THF 120 °C, the reaction between tert-butane- 70 °C,16h O sulfinamide (1) and arylbromides with ox- O 66 67:99%, 90:10 dr azolidines as ortho-substituents.[62] Excess sulfinamide and long reaction times were Scheme 14. Representative examples of Pd(0)-catalyzed allylic substitutions with tert-butanesul- however necessary. The same catalytic finamides. The French connecTion CHIMIA 2016, 70, No. 1/2 91

with allylic carbonates with the same Scheme 15. Pd(ii)- Pd(OAc) /dppe catalytic system and in the Pd(TFA)2 (10 mol%) catalyzed aerobic 2 LiOAc (1.0 equiv.) absence of additional base. Cross-coupling O O oxidative cyclization O (1 atm) S 2 S of alkenes with tert- reactions between 64 and 2- or 3-substitut- tBu NH Me tBu N ed allylic carbonates were achieved in high DMSO, 3ÅMS butanesulfinamide nucleophiles. yields. As illustrated with the formation of 50 °C,24h 65, in the case of 3-substituted carbonates, 68 69:68%, 88:12 dr complete regio- and stereoselectivity in fa- Pd(TFA)2 (10 mol%) Ph LiOAc (1.0 equiv.) vor of the E-configured linear allylic sul- O O O (1 atm) finamides was obtained. S Ph 2 S tBu NH tBu N Since it was demonstrated that the sul- DMSO, 3ÅMS fur atom remains configurationally stable Me 50 °C,24h Me throughout the allylation process, the pos- 70 71:85%, >95:05 dr sibility to achieve chiral induction with the tert-butanesulfinyl chiral auxiliary was Pd(TFA)2 (10 mol%) LiOAc (1.0 equiv.) O O also considered. The intermolecular reac- O (1 atm) S 2 S tion with racemic secondary allylic car- tBu NH tBu N bonates was sluggish and the levels of dia- DMSO, 3ÅMS Me 50 °C,24h Me stereoselectivity only moderate. However, the intramolecular N-allylation of N-acyl 72 73:78%, >95:05 dr sulfinamide 66 to provide pyrrolidinone 67 occurred in excellent yield and with very Received: July 6, 2015 good stereoselectivity.[66] tBu tBu S S Another Pd-catalyzed process for O NH AgOAc (10 mol%) O N which N-alkyl tert-butanesulfinamides [1] Leading reviews: a) D. Morton, R. A. Stockman, O CH2Cl2,reﬂux O have proved to be competent nitrogen nu- N N Tetrahedron 2006, 62, 8869; b) G.-Q. Lin, M.- cleophiles is the Pd(ii)-catalyzed aerobic Tr Tr H. Xu, Y.-W. Zhong, X.-W. Sun, Acc. Chem. oxidative cyclization of alkenes (Scheme 74 75:75% Res. 2008, 41, 831; c) F. Ferreira, C. Botuha, F. Chemla, A. Perez-Luna, Chem. Soc. Rev. 2009, 15).[67] For instance, the cyclization of tBu tBu 38, 1162; d) M. T. Robak, M. A. Herbage, J. A. sulfinamide 68 having a tethered Z-alkene S O S O NH AgBF4 (1.0 equiv.) N Ellman, Chem. Rev. 2010, 110, 3600. and no α-substituent leads in good yields • [2] X. Lv, Q. Xiang, Q. Zeng, Org. Prep. Proc. Int. to the formation of 2-vinyl pyrrolidinone THF,rt 2014, 46, 164. 69 on treatment with Pd(TFA) (10 mol%) O O [3] For an elegant method to perform N-alkylation 2 76 77:75% with alcohols through a Ru-catalyzed and LiOAc (1 equiv.) under an oxygen at- autotransfer process, see; R. Cano, D. J. Ramon, mosphere in DMSO at 50 °C. A diastereo- Scheme 16. Ag(i)-catalyzed intramolecular hy- M. Yus, J. Org. Chem. 2011, 76, 5547. meric ratio of 88:12 is obtained, thereby droamination reactions. [4] M. Martjuga, S. Belyakov, E. Liepinsh, E. Suna, evidencing that the tert-butanesulfinyl J. Org. Chem. 2011, 76, 2635. group can act efficiently as chiral auxiliary. [5] Representative examples in the context of synthetic applications: a) R. S. Grainger, E. J. The method is applicable to the cyclization Welsh, Angew. Chem. Int. Ed. 2007, 46, 5377; of α-branched sulfinamides, as illustrated 5. Conclusion b) E. A. Illardi, A. Zakarian, Chem. Asian. J. with the formation of 71 and 73. In this 2011, 6, 2260; c) A. R. Healy, M, Izumikawa, case the stereoselectivity is governed by The collection of reactions described in A. M. Z. Slawin, K. Shin-ya, N. J. Westwood, Angew. Chem. Int. Ed. 2015, 54, 4046. the α-stereocenter and cis-2,5-disubsti- this review shows that a fertile area of the [6] a) V. R. Arava, L. Gorentla, P. K. Dubey, tuted pyrrolidines are formed in excellent chemistry of tert-butanesulfinamide has Belstein J. Org. Chem. 2012, 8, 1366; b) O. O. yields and stereoselectivities regardless of grown in the shade of N-tert-butanesulfinyl Fadeyi, T. J. Senter, K. N. Hahn, C. W. Lindsley, the relative configuration between the sul- imines. Chem. Eur. J. 2012, 18, 5826. fur atom and the α-stereocenter. In asymmetric synthesis, carbon–nitro- [7] a) B. Helal, F. Ferreira, C. Botuha, F. Chemla, A. Perez-Luna, Synlett 2009, 3115; b) F. gen bond forming reactions using tert-bu- Ferreira, C. Botuha, F. Chemla, A. Perez-Luna, 4.3 Hydroamination Reactions of tanesulfinamides as nitrogen nucleophiles J. Org. Chem. 2009, 74, 2238; c) T. J. Senter, tert-Butanesulfinamides were initially implemented to further elab- O. O. Fadeyi, C. W. Lindsley, Org. Lett. 2012, Very recently, the possibility to use tert- orate adducts obtained from stereoselective 14, 1869; d) Q. Liu, Y.-A. Zhang, P. Xu, Y. Jia, J. Org. Chem. 2013, 78, 10885; e) C. Anton- butanesulfinamides as nitrogen nucleo- additions of nucleophiles to N-tert-butane- Torrecillas, I. Bosque, J. C. Gonzalez-Gomez, philes for intramolecular hydroamination sulfinyl imines and have proved particular- M. I. Loza, J. Brea, J. Org. Chem. 2015, 80, reactions under Ag(i) catalysis has been ly useful for the construction of nitrogen 1284. established (Scheme 16).[68] The cycliza- heterocyles by heterocylization reactions. [8] In situ N-allylation; S. Zhao, R. B. Andrade, J. tions of alkyne 74 to produce spiro indole In the last five years, important seminal Am. Chem. Soc. 2013, 135, 13334. [9] R. A. Bauer, C. M. DiBlasi, D. S. Tan, Org. Lett. 75 in the presence of a catalytic amount of contributions have unveiled new aspects of 2010, 12, 2084. AgOAc,[68a] and of allene 76 to obtain 77 this reactivity that will certainly pave the [10] S.-S. Jin, H. Wang, T.-S. Zhu, M.-H. Xu, Org. by treatment with a stoichiometric amount way for new applications in synthesis. On Biomol. Chem. 2012, 10, 1764. of AgBF ,[68b] provide a proof-of-concept the one hand, it has been demonstrated that [11] a) B. Denolf, S. Mangelinckx, K. W. Tornroos, 4 N. De Kimpe, Org. Lett. 2006, 8, 3129; b) B. for this chemistry for which the scope is chiral induction can be obtained using tert- Denolf, E. Leemans, N. De Kimpe, J. Org. yet to be established. butanesulfinamides as chiral nucleophiles Chem. 2007, 72, 3211. in a range of transformations. On the other [12] G. Callebaut, F. Colpaert, M. Nonn, L. Kiss, hand, tert-butanesulfinamides have proved R. Sillanpaa, K. W. Tornroos, F. Fulop, N. De suitable nitrogen donors for a variety of Kimpe, S. Mangelinckx, Org. Biomol. Chem. 2014, 12, 3393. metal-mediated carbon–nitrogen cross- [13] O. Pablo, D. Guijarro, M. Yus, J. Org. Chem. coupling reactions. 2013, 78, 9181. 92 CHIMIA 2016, 70, No. 1/2 The French connecTion

[14] Y. Li, T. Zheng, W. Wang, W. Xu, Y. Ma, S. [33] R. Luisi, V. Capriati, S. Florio, P. Di Cunto, B. c) Y. Tan, X. Yang, W. Liu, X. Sun, Tetrahedron Zhang, H. Wang, Z. Sun, Adv. Synth. Catal. Musio, Tetrahedron 2005, 61, 3251. Lett. 2014, 55, 6105. 2012, 354, 308. [34] a) T. Moragas Sola, I. Churcher, W. Lewis, R. A. [48] X. Yang, C. Dong, J. Chen, Y. Ding, Q. Liu, X. [15] D. Li, Y. Li, Z. Chen, H. Shang, H. Li, X. Ren, Stockman, Org. Biomol. Chem. 2011, 9, 5034; Ma, Q. Zhang, Y. Chen, Chem. Asian J. 2013, 8, RSC Adv. 2014, 4, 14254. b) T. Moragas, I. Churcher, W. Lewis, R. A. 1213. [16] J. A. Burkhard, B. Wagner, H. Fischer, F. Stockman, Org. Lett. 2014, 16, 6290. [49] H. Wu, F. Xue, X. Xiao, Y. Qin, J. Am. Chem. Schuler, K. Müller, E. M. Carreira, Angew. [35] a) G. Varchi, A. Guerrini, A. Tesei, G. Soc. 2010, 132, 14052. Chem. Int. Ed. 2010, 49, 3524. Brigliadori, C. Bertucci, M. Di Donato, G. [50] Y. Wang, Q.-F. He, H.-W. Wang, X. Zhou, Z.-Y. [17] E. Leemans, S. Mangelinckx, N. De Kimpe, Castoria, ACS Med. Chem. Lett. 2012, 3, 454; b) Huang, Y. Qin, J. Org. Chem. 2006, 71, 1588. Chem. Commun. 2010, 46, 3122. H. Rodriguez-Solla, C. Concellon, N. Alvaredo, [51] S. Fustero, S. Monteagudo, M. Sanchez- [18] a) L. R. Reddy, M. Prashad, Chem. Commun. R. Llavona, S. Garcia-Granda, M. Rosario Diaz, Rosello, S. Flores, P. Barrio, C. del Pozo, Chem. 2010, 46, 222; b) L. R. Reddy, S. G. Das,Y. Liu, R. G. Soengas, Synlett 2013, 24, 181. Eur. J. 2010, 16, 9835. M. Prashad, J. Org. Chem. 2010, 75, 2236; c) [36] Y. Li, Y. Ma, Z. Lu, L. Wang, X. Ren, Z. Sun, [52] S. Fustero, L. Herrera, R. Lazaro, E. Rodriguez, L. R. Reddy, A. P. Gupta, E. Villhauer, Y. Liu, J. Tetrahedron Lett. 2012, 53, 4711. M. A. Maestro, N. Mateu, P. Barrio, Chem. Eur. Org. Chem. 2012, 77, 1095. [37] Y. Li, H. Huang, Z. Wang, F. Yang, D. Li, B. J. 2013, 19, 11776. [19] I. Bosque, J. C. Gonzalez-Gomez, M. I. Loza, J. Qin, X. Ren, RSC Adv. 2014, 4, 969. [53] S. Fustero, J. Moscardo, M. Sanchez-Rosello, Brea, J. Org. Chem. 2014, 79, 3982. [38] a) T. Boultwood, D. P. Affron,A. D. Trowbridge, E. Rodriguez, Org. Lett. 2010, 12, 5494. [20] J. Louvel, C. Botuha, F. Chemla, E. Demont, J. A. Bull, J. Org. Chem. 2013, 78, 6632; b) D. [54] M. Guerola, M. Sanchez-Rosello, C. Mulet, C. F. Ferreira, A. Perez-Luna, Eur. J. Org. Chem. Li,Y. Li, Z. Chen, H. Shang, H. Li, X. Ren, RSC del Pozo, S. Fustero, Org. Lett. 2015, 17, 960. 2010, 2921. Adv. 2014, 4, 14254. [55] T. P. Tang, J. A. Ellman, J. Org. Chem. 2002, 67, [21] With tBuOK: a) X.-N. Song, Z.-J. Yao, [39] Selected references: a) J. L. Garcia Ruano, I. 7819. Tetrahedron 2010, 66, 2589; With NaH/15- Fernandez, M. del Prado Catalina, A. Alcudia [56] a) C. E. Jakobsche, G. Peris, S. J. Miller, Crown-5: J. Louvel, F. Chemla, E. Demont, F. Cruz, Tetrahedron: Asymmetry 1996, 7, 3407; Angew. Chem. Int. Ed. 2008, 47, 6707; b) K. N. Ferreira, A. Perez-Luna, Org. Lett. 2011, 13, b) D. Morton, D. Pearson, R. A. Field, R. Hahn, O. O. Fadeyi, H. P. Cho, C. W. Lindsley, 6452. A. Stockman, Org. Lett. 2004, 6, 2377; c) Tetrahedron Lett. 2012, 53, 3577; c) C. Anton- [22] C. E. Jakobsche, A. Choudhary, S. J. Miller, R. D. Morton, D. Pearson, R. A. Field, R. A. Torrecillas, J. C. Gonzalez-Gomez, Org. T. Raines, J. Am. Chem. Soc. 2010, 132, 6651. Stockman, Chem. Commun. 2006, 1833; d) Biomol. Chem. 2014, 12, 7018. [23] a) A. Voituriez, F. Ferreira, A. Perez-Luna, F. M. G. Unthank, N. Hussain, V. K. Aggarwal, [57] I. Bosque, E. Bagdatli, F. Foubelo, J. C. Chemla, Org. Lett. 2007, 9, 4705; b) J. Louvel, Angew. Chem. Int. Ed. 2006, 45, 7066; e) D. C. Gonzalez-Gomez, J. Org. Chem. 2014, 79, F. Chemla, E. Demont, F. Ferreira, A. Perez- Forbes, S. V. Bettigeri, Chem. Commun. 2009, 1796. Luna, A. Voituriez, Adv. Synth. Catal. 2011, 1882. [58] For an example of azetidine formation possibly 353, 2137. [40] J.-C. Zheng, W.-W. Liao, X.-X. Sun, X.-L. Sun, driven by the Thorpe-Ingold effect, C. Guerot, [24] a) N. S. S. Reddy, A. S. Reddy, J. S.Yadav, B. V. Y. Tang, L.-X. Dai, J.-G. Deng, Org. Lett. 2005, B. H. Tchitchanov, H. Knust, E. M. Carreira, S. Reddy, Tetrahedron Lett. 2012, 53, 6916; b) 7, 5789. Org. Lett. 2011, 13, 780. N. S. S. Reddy, B. J. M. Reddy, B. V. S. Reddy, [41] B. J. Backes, D. R. Dragoli, J. A. Ellman, J. [59] A. A. Kudale, P. Anaspure, F. Goswani, M. Tetrahedron Lett. 2013, 54, 4228; c) N. S. S. Org. Chem. 1999, 64, 5472. Voss, Tetrahedron Lett. 2014, 55, 7219. Reddy, B. V. S. Reddy, Tetrahedron Lett. 2014, [42] M. T. Robak, M. A Herbage, J. A. Ellman, [60] A. Prakash, M. Dibakar, K. Selvakuar, K. 55, 3157; d) R. A. Babu, N. S. S. Reddy, B. J. Tetrahedron 2011, 67, 4412. Ruckmani, M. Sivakumar, Tetrahedron Lett. M. Reddy, B. V. S. Reddy, Synthesis 2014, 46, [43] L. Mistico, E. Ay, V. Huynh, A. Bourderioux, 2011, 52, 5625. 2794. F. Chemla, F. Ferreira, J. Oble, A. Perez-Luna, [61] J. Baffoe, M. Y. Hoe, B. B. Touré, Org. Lett. [25] F. Colpaert, S. Mangelinckx, N. De Kimpe, J. G. Poli, G. Prestat, J. Organomet. Chem. 2014, 2010, 12, 1532. Org. Chem. 2011, 76, 234. 760, 124. [62] P. I. Binda, S. Abbina, G. Du, Synthesis 2011, [26] K. Brak, J. Ellman, Org. Lett. 2010, 12, 2004. [44] M. T. Robak, M. Trincado, J. A. Ellman, J. Am. 2609. [27] F. Colpaert, S. Mangelinckx, E. Leemans, B. Chem. Soc. 2007, 129, 15110. [63] B.-L. Chen, B. Wang, G.-Q. Lin, J. Org. Chem. Denolf, N. De Kimpe, Org. Biomol. Chem. [45] a) K. L. Kimmel, M. T. Robak, J. A. Ellman, 2010, 75, 941. 2010, 8, 3251. J. Am. Chem. Soc. 2009, 131, 8754; b) K. L. [64] X. Sun, X. Tu, C. Dai, X. Zhang, B. Zhang, Q. [28] D. M. Hodgson, J. Kloesges, B. Evans, Org. Kimmel, J. D. Weaver, J. A. Ellman, Chem. Sci. Zeng, J. Org. Chem. 2012, 77, 4454. Lett. 2008, 10, 2781. 2012, 3, 121. [65] Z. Dong, S. G. Pyne, Sulfur Letters 2002, 25, [29] J. Liu, J. Hu, Chem. Eur. J. 2010, 16, 11443. [46] a) K. W. Kells, J. M. Chong, Org. Lett. 2003, 37. [30] F. A. Davis, T. Ramachandar, Y. Wu, J. Org. 5, 4215; b) G. Dirscherl, P. Rooshenas, P. R. [66] Unpublished results from our group. Chem. 2003, 68, 6894. Schreiner, F. Lamaty, B. König, Tetrahedron [67] J. E. Redford, R. I. McDonald, M. L. Rigsby, [31] a) F. Chemla, F. Ferreira, Synlett 2004, 983; b) 2008, 64, 3005; c) E. Deu, M. J. Leyva, V. E. J. D. Wiensch, S. S. Stahl, Org. Lett. 2012, 14, F. Chemla, F. Ferreira, J. Org. Chem. 2004, 69, Albrow, M. J. Rice, J. A. Ellman, M. Bogyo, 1242. 8244; c) F. Ferreira, M. Audouin, F. Chemla, Chem. Biol. 2010, 17, 808. [68] a) D. Chen, M.-H. Xu, Chem. Commun. 2013, Chem. Eur. J. 2005, 11, 5269. [47] a) M. F. Jacobsen, T. Skrydstrup, J. Org. Chem. 49, 1327; b) L. Su, T.-S. Zhu, M.-H. Xu, Org. [32] W.-J. Liu, Y.-H. Zhao, X.-W. Sun, Tetrahedron 2003, 68, 7112; b) A. Shen, M. Liu, Z.-S. Jia, Lett. 2014, 16, 4118 Lett. 2013, 54, 3586. M.-H. Xu, G.-Q. Lin, Org. Lett. 2010, 12, 5154;