Christina Koerber

Louis Fensterbank

Max Malacria

Comptes Rendus Chimie

Preliminary communicationReactivity of NBS towardsN-allyl glycinyl derivativesChristina Koerber, Louis Fensterbank *, Max Malacria *Laboratoire de chimie organique de synthèse associé au CNRS, université Pierre-et-Marie-Curie, 4, place Jussieu, tour 44–54,case 229, 75252 Paris cedex 05, FranceReceived 6 September 2002; accepted 9 April 2003AbstractThe reaction of precursors3 with NBS in radical conditions does not yield any azetidine resulting from a 4-exo radicalcyclisation with bromine atom transfer, or any brominated product at the glycinyl position. Instead, dibrominated adducts4 andaminals5 have been formed in good yields. We have investigated the mechanism of this puzzling transformation and shown thatthe homolytic abstraction of a hydrogen atom by a Br• radical does not take place at the capto-dative position but at the allylicone. The resultinga-bromo derivative8 would then evolve into an iminium intermediate with concomitant production ofbromine and of a succinimidyl anion, which explains the formation of products4 and5. To cite this article: C. Koerber et al.,C.R. Chimie 6 (2003).© 2003 Académie des sciences. Published by Éditions scientifiques et médicales Elsevier SAS. All rights reserved.RésuméEn vue d’accéder à divers composés de type azétidine, nous présentons ici nos résultats sur les possibilités de cyclisation deradicaux glycinyles en conditions de transfert d’atome. En présence de NBS et en conditions de réaction radicalaire, nousobtenons à partir des précurseurs3, les produits dibromés4 et les aminals5 dans des proportions voisines, mais aucune trace duproduit bromé en position glycinyle, ni de l’azétidine résultant de la cyclisation 4-exo-trig. Nous avons voulu aller plus loin dansla compréhension de cette réactivité et avons pu démontrer que l’arrachement homolytique d’un atome d’hydrogène par unradical Br• n’a pas lieu en position capto-dative, mais en position allylique. Le produita-bromé8 résultant évoluerait ensuitepour engendrer un intermédiaire de type iminium avec production concomitante de dibrome et d’un anion succinimidyle,expliquant la formation des produits4 et 5. Pour citer cet article : C. Koerber et al., C.R. Chimie 6 (2003).© 2003 Académie des sciences. Published by Éditions scientifiques et médicales Elsevier SAS. All rights reserved.Keywords: glycinyl radical; hydrogen abstraction; iminium; allylic amines;N-bromo succinimide;a aminoacidMots clés : radical glycinyle ; arrachement d’hydrogène ; iminium ; amines allyliques ;N-bromo succinimide ;a aminoacide* Corresponding authors.E-mail addresses: fensterb@ccr.jussieu.fr (L. Fensterbank), malacria@ccr.jussieu.fr (M. Malacria).C. R. Chimie 6 (2003) 451–455© 2003 Académie des sciences. Published by Éditions scientifiques et médicales Elsevier SAS. All rights reserved.doi:10.1016/S1631-0748(03)00068-71. IntroductionOver the last couple of years, we have been inter-ested in the development of asymmetric radical cycli-sation [1, 2]. We have based our approach on the use ofsulfoxides as temporary chiral auxiliaries. A sequenceinvolving a radical cyclisation followed by ab-elimination of the sulfinyl moiety could serve inasymmetric intramolecular vinylations to provideenantiopure alkylidene cyclopentanes [3, 4]. Wewanted to extend this process to the synthesis of four-membered rings and notably examine the radical cycli-sation of a glycinyl radical 1 onto a vinylsulfoxide(Fig. 1). In this case, the sulfinyl group would ensurethe diastereoselectivity of the formation of thea-aminoacid stereogenic centre and its rapidb-elimination [5] after cyclisation (radical intermedi-ate 2) would constitute a sufficient driving force for theconstruction of this strained structure. This new radicalprocess could find a lot of applications such as thepreparation of the polyoximic acid that is the amino-acid core of the natural product polyoxin A [6].2. Results and discussionWe first examined precursors with no sulfinyl groupand incorporating a styryl moiety in order to activatethe radical cyclisation step. Moreover, we wished toperform these reactions under atom transfer reactions[7]. The synthesis of glycinyl bromide derivatives isrelatively well described in the literature and is gener-ally performed under radical reaction conditions [8, 9].We therefore submitted precursors of type 3 to thefollowing reagents and conditions: AIBN (10 mol%),NBS (1 equiv) in refluxing CCl4 for 1 h. However, toour surprise, we did not observe any intermediate bro-moglycinyl derivative nor the expected azetidine ad-duct resulting from the radical cyclisation. Instead, weisolated the dibromo derivative 4 and the succinimidyladduct 5 in good overall yield in a ratio close to 1:1(Fig. 2).This rather unexpected turnout of the reaction led usto investigate further substrates to confirm these find-ings. Since the N-alkylation of alkoxycarbonyl-protected glycines gave generally poor yields, the pro-tected group was changed for further studies, and weadopted arylsulfonyl based ones, avoiding tosyl be-cause under radical conditions the benzylic positioncould be brominated. The synthesis of the precursorswas straightforward and is described in Fig. 3. Theyields of the N-alkylation step are listed in Table 1.We first concentrated on the behaviour of precursor3b that gave the same result and varied the reactionconditions to delineate the optimum conditions for theformation of dibromo derivative 4b and the succinim-idyl adduct 5b (Fig. 4 and Table 2). It should also beFig. 1Fig. 2Fig. 3Table 1N-alkylation providing precursors 3.Entry R yield product1 Ph 87% 3b2 NO2–Ph 80% 3c3 Camph 89% 3d452 C. Koerber et al. / C. R. Chimie 6 (2003) 451–455noted that the structure of aminal 5b was confirmed byan X-ray analysis.Some facts can be observed from these experiments.It appears that the starting material always partitionsbetween the two adducts 4b and 5b in a close 1:1 ratio.The concentration has no influence on this productdistribution (entries 1 & 2). With two equiv. of NBS,one observes the same product distribution (entry 3).The reaction can be induced thermally (AIBN, reflux)or photolytically by a 300-W sunlamp (entries 1 & 4).The reaction is also very efficient in chloroform (en-try 5). An interesting finding was that with non-distilled chloroform stabilized with ethanol, adduct 5bcould not be isolated; instead, some other product isobserved in 33% yield whose structure was assigned as6 (entry 6).In CH2Cl2, under thermal conditions (AIBN, re-flux), the reaction occurs very slowly because the tem-perature is probably not sufficient enough to trigger anefficient radical process (entry 7).The influence of the sulfonyl protecting groups(Table 3) was next examined. In the case of the nosylgroup (Ns), two equivalents of NBS were needed forcomplete consumption of the starting material 3c(Table 3, entry 1). No diastereoselectivity could beobserved when a chiral auxiliary was introduced. Pre-cursor 3d (Table 3, entry 2) gave an equimolar diaste-reomeric ratio of adducts 4d and 5d.A question remained to be solved: the functionaliza-tion of the obtained adducts 4 and 5 strongly suggeststhat the aminoacid methylene of the glycine moietyremains intact towards the radical abstraction. To havemore evidence on this, we examined the behaviour ofthe dideuterated precursor 3bD, easily obtained from3b by exchange with NaOEt/DOEt (transesterificationalso occurred). A mixture of dideuterated adducts 4bDand 5bD retaining the deuterium incorporation at theaminoacid site was obtained.This led us to the mechanism proposal displayed inFig. 5. After generation of the bromine radical [10],hydrogen abstraction takes place at the allylic positionrather than at the glycinyl position, a finding that isconsistent with the recent work of Bertrand with thiylradicals [11]. Comparison of the bond-dissociation en-ergies (BDE), i.e. 81–82 kcal mol–1 for allylic amines[12], and 76–83 kcal mol–1 for the glycinyl position[13,14,15] does not allow to rationalize this completechemoselectivity of H-abstraction, but in our case thestyryl moiety might bring additional stabilization [16].Bromination of the intermediate radical 7 would givebirth to an a-bromo intermediate 8, which immediatelysuffers bromide elimination, producing a highly stabi-lized iminium species 9 [17, 18], followed by theformation of a succinimidyl anion and bromine. Thesetwo new reactants would then respectively add to theiminium intermediate (adduct 5) and brominate thestyryl moiety (adduct 4).An alternative pathway could be the oxidation [19]of the a-amino radical 7 with concomitant electrontransfer to bromine, which yields the formation of theiminium intermediate 9 and of the bromide anion, andthen the same ionic steps operate.Fig. 4Table 2Optimisation of the reaction conditions.Entry Solvent Condition Concentration Eq. numbers 3b 4b 5b1 CCl4 D, AIBN 0.05 M 1 — 46% 40%2 CCl4 D, AIBN 0.02 M 1 — 46% 44%3 CCl4 D, AIBN 0.05 M 2 — 42% 45%4 CCl4 h m, Ar 0.05 M 1 — 40% 38%5 CHCl3 D, AIBN 0.05 M 1 — 50% 50%6 CHCl3a D, AIBN 0.05 M 1.1 — 50% —b7 CH2Cl2 D, AIBN 0.05 M 1 62% 22% 16%D = reflux; hv = 300-W sun lamp;Ar = bubbling argon through the mixture. a Undistilled chloroform stabilized with EtOH. b Compound 6 wasisolated in 30% yield. c Determined by 1H NMR.Table 3Variations of the sulfonyl protecting group.Entry conditions precursor R 4 51 AIBN, CCl4, D 3c Ns 4c, 50% 5c, 30%2 AIBN, CCl4, D 3d Camph 4d, 50% 5d, 41%453C. Koerber et al. / C. R. Chimie 6 (2003) 451–455Finally, an interesting observation was made when a1:1 mixture of 3b and 5b was treated with one equiv ofBr2. After 1 h in refluxing CCl4, 5b remained un-touched while 3b was 75% converted to 4b, showingthat bromine, probably for steric reasons, preferablyadds to 3b rather than to the succinimido adduct 5b.Naturally, this reaction could take place with a plainalkyl substituted amine 10 leading to brominated andsuccinimido adducts 11 and 12 in good yields (Fig. 6).Structure of 8 was confirmed by an X-ray analysis.3. ConclusionIn conclusion, N-allyl glycinyl derivatives undergohomolytic hydrogen abstraction at the allylic positionand not at the a-aminoacid captodative one. Subse-quent formation of an iminium intermediate triggers anionic path with bromination of the starting material andformation of an aminal adduct. This intermediate canalso be trapped with other nucleophiles (alcohols) andwe are now directing our efforts towards the design ofa clean and efficient N-allyl functionalization reaction.These findings augur well for the development of fur-ther selective C–H activation reactions, involving theNBS reagent and allowing subsequent polar processes.The system we have studied also represents a mimic ofthe aerobic oxidation of nitrogen containing substratesby shedding new light on competitive homolytic hy-drogen abstractions.4. Typical experimental procedurePrecursor 3b (172 mg, 0.5 mmol), NBS (90 mg,0.5 mmol) and AIBN (6 mg, 0.05 mmol) in 10 ml CCl4were refluxed for 1 h. The cold, crude mixture waspurified by column chromatography (PE/EA: 60/40 →0/100) and yielded 4b in 46% (117 mg) as a colourlessoil, which crystallized slowly and 5b in 40% (90 mg)as colourless oil, which crystallized slowly (recrystal-lisation from PE/EE).Dibromo adduct 4b: m.p.: 99 °C, Rf: 0.54 (PE/EA:60/40). 1H–NMR (CDCl3, 200 MHz): d = 3.32 (dd,J = 16.0, 9.5 Hz, 1 H, NCHH), 3.47 (s, 3 H, OCH3),4.23 (d, J = 18.6 Hz, 1 H, NHHCO), 4.39 (d,J = 18.6 Hz, 1 H, NCHHCO), 4.51 (dd, J = 16.0,1.8 Hz, 1 H, NCHH), 4.85 (dt, J = 9.5, 1.8Hz, 1 H,BrCH), 4.93 (d, J = 9.5 Hz, 1 H, BrCH), 7.25–7.80 (m,10 H, arom.). 13C–NMR (CDCl3, 50 MHz): d = 50.6(CH2), 52.1 (OCH3), 54.2 (BrCH), 54.8 (CH2), 56.4(BrCH), 127.6 (CH arom.), 126.9 (CH arom.), 128.5(CH arom.), 128.7 (CH arom.), 128.9 (CH arom.),133.0 (CH arom.), 138.4 (C arom.), 139.0 (C arom.),169.0 (C=O).Anal. calc. for C18H19Br2NO4S (505.22): C, 42.79;H, 3.79; N, 2.77. Found: C, 42.62 ; H, 3.92; N, 2.72.Aminal 5b: m.p.: 125.2 °C, Rf: 0.13 (PE/EA:60/40). 1H–NMR (CDCl3, 200 MHz): d = 2.49 (s, 4 H,CH2CH2), 3.53 (s, 3 H, OCH3), 4.52 (s, 2 H, CH2), 6.28(dd, J = 15.9 Hz, J = 5.6 Hz, 1 H, = CH), 6.43 (d,Fig. 5Fig. 6454 C. Koerber et al. / C. R. Chimie 6 (2003) 451–455J = 15.9 Hz, 1 H, = CH), 6.54 (d, J = 5.6 Hz, 1 H,NCH), 7.22 (s, 5 H, arom.), 7.40–7.95 (m, 5 H, arom.).13C–NMR (CDCl3, 50 MHz): d = 27.8 (CH2CH2), 47.1(CH2), 52.1 (OCH3), 64.0 (NCH), 119.3 (= CH), 126.7(CH arom.), 127.8 (CH arom.), 128.5 (CH arom.),128.7 (CH arom.), 128.8 (CH arom.), 133.1 (CHarom.), 134.8 (C arom.), 135.8 (= CH), 139.2 (Carom.), 170.2 (C = O), 176.2 (NC = O).Supplementary MaterialX-ray data of 5b and 11 including list of length,angles, ORTEP figures. This supplementary materialhas been sent to the Cambridge Crystallographic DataCentre, 12 Union Road, Cambridge CB2 1EZ, UK, andcan be obtained by contacting the CCDC (quoting thearticle details and the corresponding numbers: CCDC204545 for 5b, CCDC 204546 for 11.AcknowledgementsCK thanks the EU for a Marie-Curie fellowship.The authors thank Prof. Michèle Bertrand and DrStéphane Gastaldi (University of Aix–Marseilles–3,France) for fruitful discussions and Dr Jacqueline Vais-sermann (UMPC, Paris, France) for the X-ray analysisof 5b and 11. The authors thank one of the referees forhelpful comments on the mechanism proposal.References[1] For a review: Curran D.P., Porter N.A., Giese B., Stereochem-istry of Radical Reactions, VCH, Weinheim, Germany, 1995.[2] M. Zahouily, M. Journet, M. Malacria, Synlett (1994) 366.[3] E. Lacôte, B. Delouvrié, L. Fensterbank, M. Malacria, Angew.Chem. Int. Engl. Ed. 37 (1998) 2116.[4] B. Delouvrié, L. Fensterbank, E. Lacôte, M. Malacria, J. Am.Chem. Soc. 121 (1999) 11395.[5] V. Mouriès, B. Delouvrié, E. Lacôte, L. Fensterbank, M. Ma-lacria, Eur. J. Org. Chem. (2002) 1776.[6] S. Hanessian, J.-M. Fu, Y. Tu, K. Isono, Tetrahedron Lett. 34(1993) 4153.[7] J. Byers, in: P. Renaud, M.-P. Sibi (Eds.), Radicals in OrganicSynthesis, vol. 1, Wiley–VCH, Weinheim, Germany, 2001,p. 72.[8] C.J. Easton, Chem. Rev. 97 (1997) 53.[9] M. Ricci, P. Blakskjaer, T. Skrydstrup, J. Am. Chem. Soc. 122(2000) 12413.[10] R. Brückner, Mécanismes réactionnels en chimie organique,DeBoeck Université, Paris, 1999.[11] M.-P. Bertrand, S. Escoubet, S. Gastaldi, V.I. Timokhin,Chem. Commun. (2002) 216.[12] G.W. Dombrowski, J.P. Dinnocenzo, S. Farid, J.L. Goodman,I.R. Gould, J. Org. Chem. 64 (1999) 427.[13] A. Rauk, D. Yu, D.A. Armstrong, J. Am. Chem. Soc. 120(1998) 8848.[14] For other values, see: F. Himo, Chem. Phys. Lett. 328 (2000)270.[15] J. Fossey, D. Lefort, J. Sorba, Free Radicals in Organic Chem-istry, Masson, Paris, 1995.[16] See also for a similar hydrogen abstraction in cyclic serieswith peroxides: J.M. Tanko, R. Friedline, N.K. Suleman, N.J.Castagnoli, J. Am. Chem. Soc. 123 (2001) 5808.[17] M.E. Flanagan, R.M. Williams, J. Org. Chem. 60 (1995) 6791.[18] C. Caristi, A. Ferlazzo, M. Gattuso, J. Chem. Soc., PerkinTrans. I (1984) 281 For a study on N,N-dimethylamido andN,N-dimethylamino derivatives see.[19] P. Renaud, L. Giraud, Synthesis (1996) 913–926.455C. Koerber et al. / C. R. Chimie 6 (2003) 451–455

Reactivity of NBS towards <i>N</i>-allyl glycinyl derivatives

https://comptes-rendus.academie-sciences.fr/chimie/item/10.1016/S1631-0748(03)00068-7.pdf

Reactivity of NBS towards <i>N</i>-allyl glycinyl derivatives

Abstract

Similar works

Full text

Available Versions

Comptes Rendus Chimie