Myers Chem 115 Cyclobutane Synthesis Reviews: • Intramolecular [2+2] Cycloadditions: Hoffmann, N. Chem. Rev. 2008, 108, 1052–1103. • Intramolecular [2+2] cycloadducts are readily formed. Tethers are typically 2 to 4 atom: Lee-Ruff, E.; Mladenova, G. Chem. Rev. 2003, 103, 1449–1484. Crimmins, M. T. Chem. Rev. 1988, 88, 1453–1473. Bach, T. Synthesis 1998, 683–703. O CH3 h$ Challenges: • Cyclobutanes are highly strained: O hexanes 98%, dr = 92:8 OBz H3C O * OBz H3C H OBz minimize non-bonded interactions Strain energy in kcal/mol 27.5 26.3 6.2 0.1 H3C H3C H H3C • • Wiberg, K. B. Angew. Chem. Int. Ed. 1986, 25, 312–322. CH3 Synthetic Methods For the Construction of Cyclobutanes: C6H6, 80 °C 50% #8,9-capnellene • [2+2] Cycloadditions: H3C BF3•Et2O CH3 CH3 6 steps H3C CH3 H H3C O epi-precapnelladiene O H CH3 1. LHMDS MeI (2 equiv) THF –70 " 0 ºC 2. KOH, DMSO 25 ºC, 36% H • Suprafacial [2+2] cycloadditions are photochemically allowed but thermally forbidden. • Frontier Molecular Orbital Analysis: Birch, A. M.; Pattenden, G. J. Chem. Soc., Chem. Commun. 1980, 1195–1197. Birch, A. M.; Pattenden, G. J. Chem. Soc., Perkin Trans. 1, 1983, 1913–1917. • Intermolecular [2+2] Cycloadditions • Regioselectivity issues: head-to-tail (HT) vs. head-to-head (HH) Thermal LUMO of one ethylene unit Photochemical !* !* O X HOMO of one ethylene unit ! suprafacial [2+2] symmetry forbidden !* one ethylene unit is photoexcited O O R R suprafacial [2+2] symmetry allowed • Enones are generally used as they are more easily photoexcited than isolated olefins. h$ R HT HH • Generally: • Photoexcited enones react via the T1 (triplet excited state). • Quantum efficiencies are higher in cyclic systems due to rapid intersystem crossing. • Acyclic and macrocyclic enones are typically not suitable for [2+2] photocycloaddition because upon photoexcitation, they undergo cis/trans isomerization. HT-isomer favored when R = donor (electron donating) HH-isomer favored when R = acceptor (electron withdrawing) Danica Rankic 1 Myers Chem 115 Cyclobutane Synthesis • Ketene [2+2] Cycloadditions • An Example of Regioselectivity Governed by Electronics O O h! H3C H3C H HN H3C H3C R O H HN HN • Antarafacial [2+2] cycloadditions are thermally allowed but geometrically disfavored for most substrates. * H H3C H3C R HT R • Ketenes are linear and sterically less encumbered, making them good substrates for thermal [2+2] cycloadditions. * HH • Frontier Molecular Orbital Analysis: H R d.r. (HT : HH) CN 18 : 82 OEt 95 : 5 O C C C O C • Both HT and HH products were obtained as a mixture of two diastereomers. Suishu, T.; Shimo, T.; Somekawa, K. Tetrahedron 1997, 53, 3545–3556. • Stereoselectivity in Intermolecular [2+2] Cycloadditions • The least hindered transition state usually dominates. There is no "endo" effect, as in the DielsAlder Reaction: CH3 O H3CO2C H3C + CH3 O h!, CH2Cl2 H CO2CH3 H3C CH3 CH3 H HOMO of C=C ketene alkene • Ketenes can be generated in situ from acid chlorides: CH3 O 23 ºC, 49% LUMO of C=C=O CH3 NEt3, CH2Cl2 Cl 40 ºC, 70% CH3 O O O H CH3 CH3 O + CH3 O H CH3 HO 3.4 : 1 (separable by chromatography) H (+)-grandisol Wilson, S. R.; Phillips, L. R.; Pelister, Y.; Huffman, J. C. J. Am. Chem. Soc. 1979, 101, 7373–7379. • When the double bond is not constrained within a rigid ring system, the intermediate triplet state diradical can lead to cis/trans isomerization of the double bond: H3C Mori, K.; Miyake, M. Tetrahedron 1987, 43, 2229–2239. h!, pentane + 23 ºC, 73% H3C H3C O H3C CH3 h!, pentane + H O H3C H H3C H Cl3C O mixture of cis and trans isomers Cl O + H3C Zn, POCl3 Et2O, 40 ºC 78% Cl CH3 O H Cl 23 ºC, 63% H3C O Corey, E. J.; Bass, J. D.; LeMahieu, R.; Mitra, R. B. J. Am. Chem. Soc. 1964, 86, 5570–5583. Krepski, L. R.; Hassner, A. J. Org. Chem. 1978, 43, 2879–2882. Danica Rankic, Fan Liu 2 Myers Chem 115 Cyclobutane Synthesis • A [2+2] Cycloaddition followed by radical fragmentation provided a key intermediate to guanacastepene E: PMP O O O O O h!, i-Pr2NEt O • Examples of [2+2] Cycloaddition in Synthesis • Synthesis of pentacycloanammoxic acid, the principal lipid component of the cell membrane of the anaerobic microbe Candidatus Brocadia anammoxidans: O h!, MeCN O i-Pr 1. (COCl)2, DMF CH2Cl2, 23 ºC 4 steps –15 ºC, 78 ºC CO2H 2. CH3 Et2O, 82% CH3 i-Pr BrCCl3, 75 ºC, DMAP h!, 10 ºC, 79% t-BuOK DMSO 50 ºC, 84% O O H i-Pr CH3 O 5 steps CH3 • A late-stage coupling reaction provided access to biyouyanagin A: h!, MeCN 23 ºC, 50% Ph(H3C)2Si pentacycloanammoxic acid H CH3 H3C Mascitti, V.; Corey, E. J. J. Am. Chem. Soc. 2006, 128, 3118–3119. CH3 • A [2+2] cycloaddition/anionic oxy-Cope/electrocyclic ring opening cascade provided a key intermediate to periplanone B. Note that both diastereomers from the [2+2] cycloaddition step can be converted to the final product: O CH3 CH3 H2C • H 72%, dr = 2:1 CH3 H CH 3 CH2 CH3 CH3 2. C6H6, h! 70–75% O CH3 CH3 2'-acetonaphthone 25 ºC, 46% H H3C CH3 H H H Ph O CH3 O O O • A [2+2] photocycloaddition followed by acid-catalyzed rearrangement provided a key intermediate to steviol: 2. KH, 18-C-6 THF, 60 ºC 75% 1. toluene, 175 ºC h!, CH2Cl2 O O Ph O h!, CH2Cl2 H3C HO O H H H3C O CH3 Nicolaou, K. C.; Sarlah, D.; Shaw, D. M. Angew. Chem. Int. Ed. 2007, 46, 4708–4711. 1. Et2O, MgBr –78 ºC, 63% O h!, Et2O CH3 Shipe, W. D.; Sorensen, E. J. J. Am. Chem. Soc. 2006, 128, 7025–7035. Si(CH3)2Ph (CH2)7CO2CH3 O i-Pr H C 3 guanacastepene E O PMP O OH AcO O 12 steps CH3 1. SmI2, HMPA THF, 23 ºC 2. PhSeBr, 50% 3. mCPBA, CH2Cl2 –78 ºC, 86% Br N S ONa H3C PMP H2C O CH3 CH3 O CH3 • H3C 23 ºC, 82% CH3 HO CH2 3. AcOH, PPA 110 ºC, 62% H3C HO 1. O3, MeOH –78 ºC 2. Me2S, 23 ºC O CH3 O Schreiber, S. L.; Santini, C. J. Am. Chem. Soc. 1984, 106, 4038–4039. Cherney, E. C.; Green, J. C.; Baran, P. S. Angew. Chem. Int. Ed. 2013, 52, 9019–9022. Fan Liu 3 Myers Chem 115 Cyclobutane Synthesis • The synthesis of longifolene was accomplished via a de Mayo reaction –– a [2+2] cycloaddition followed by retro-Aldol fragmentation: • In the synthesis of ginkgolide B, three contiguous stereogenic centers were established using an intramolecular ketene [2+2] cycloaddition reaction: H3CO OCbz OCbz O h", C6H12 H2, Pd/C 15–30 ºC, 83% dr = 2:3 AcOH, 25 ºC 83% H3C O O O Ph3C O 2. n-Bu3N, toluene 110 ºC, 71–87% H CO2H O H O O HO H OH O O Longifolene H O O steps O O H3C HO O H H3C O H t-Bu OH Ginkgolide B Corey, E. J.; Kang, M.-C.; Desai, M. C.; Ghosh, A. K.; Houpis, I. N. J. Am. Chem. Soc. 1988, 110, 649– 651. Oppolzer, W.; Godel, T. J. Am. Chem. Soc. 1978, 100, 2583–2584. • Synthesis of clovene via a ketene [2+2] thermal cycloaddition: 1. H Et3N, CH3CN 80 ºC, 35–47% CO2H OH 1N NaOH acetone –30 ºC, 86% H H3C PPh3 Br– NaOt-amyl toluene, 25 ºC 88% CH3 N Cl CH3 O H 4 steps CH3 O 1. (COCl)2, C6H6 23 ºC CH3 • Synthesis of retigeranic acid via a ketene [2+2] cycloaddition followed by cyclobutane ring expansion: Li SCH3 H3CS SCH3 CO2H CH3 H SMe SMe THF, –78 ºC O H3C H H3C 2. HCl, CHCl3 66% O H3C H3C 1. (COCl)2, C6H6, 23 ºC H3C H H 2. Et3N, 23 ºC, 80 % H CH3 H3C H CH3 Li 1. CH3 H H3C H3C clovene 1. H2NNHTs, MeOH 2. BuLi, TMEDA; H3O+, 55% CH3 H H3C H3C 1. NaH, MeI, DME, 75% 2. Raney Ni, acetone, 79% O Bamford-Stevens-Shapiro Reaction H3C H3C H CH3 H H3C H CH3 CO2H H CH3 H3C 5 steps H3C H H CH3 H H3C H CH3 O retigeranic acid Funk, R. L.; Novak, P. M.; Abelman, M. M. Tetrahedron Lett. 1988, 29, 1493–1496. O Corey, E. J.; Desaid, M.; Engler, T. A. J. Am. Chem. Soc. 1985, 107, 4339–4341. SCH3 SCH3 THF, –78 ºC 73% 2. CuOTf, Et3N C6H6, 23 ºC 3. NaIO4, H2O dioxane 4. Al/Hg, THF H2O, 0 ! 23 ºC Fan Liu 4 Myers Chem 115 Cyclobutane Synthesis • Formal [2+2] Cycloadditions: Michael-Aldol Mechanism • Silyl enol ethers and !,"-unsaturated compounds form cyclobutanes in a stepwise, Lewis acidcatalyzed process. • Upon activation by triflic anhydride, C2-symmetric chiral pyrrolidine amides form keteniminium salts, which undergo thermal [2+2] cycloadditions with excellent stereoselectivities: • In the following example, the bulky tris(trimethylsilyl)silyl (TTMSS) protecting group is required to stabilize the cationic intermediate. This and the use of a bulky aluminum catalyst with the triflimide counterion suppress silyl transfer: O Tf2O, DTBMP N Ph O TTMSSO N C TfO– CH3 TTMSSO H 1. 20 # 83 ºC 2. H2O, CCl4 80 ºC, 88% 98% ee O Ph (1 mol%) OPh ClCH2CH2Cl H3C O )2AlNTf2 H3C CH3 OPh O H CH2Cl2, –40 ºC 82%, dr = 10:1 Chen, L.; Ghosez, L. Tetrahedron Lett. 1990, 31, 4467–4470. LA LA O TTMSSO • (–)-Phenylmenthol was also found to be an effective chiral auxiliary in formal [2+2] cycloadditions of silyl enol ethers and acrylates: O OPh TTMSSO OPh CH3 CH3 O OTBS O + H3C Boxer, M. B.; Yamamoto, H. Org. Lett. 2008, 7, 3127–3129. CH Ph 3 Ph H3C EtAlCl2 (20 mol%) O AlCl2Et O CH2Cl2, –78 ºC H3C • Auxiliary-Controlled Stereoselective [2+2] Cycloadditions TBSO • One of the earliest reports involved the use of (–)-phenylmenthol as a chiral auxiliary to achieve a diastereoselective [2+2] cycloaddition: CH3 H3C 110 ºC, 70% Ph CH3 CH3 H3C Ph O Cl3CCOCl Zn-Cu, Et2O 20 ºC, >70% 67% dr H3C •O CH3 CH3 O i-Pr OTBS + H3C Greene, A. E.; Charbonnier, F. Tetrahedron Lett. 1985, 26, 5525–5528. 33%, >99% de CH3 OH CH3 H 51%, >99% de Cl Cl O OR* + H O H TBSO OR* Ph OCH3 TsOH, PhCH3 OCH3 O CH3 EtAlCl2 (20 mol%) O H3C CH Ph 3 CH2Cl2, –78 ºC TBSO i-Pr H3C CH3 O OR* 91%, >99% de Takasu, K.; Nagao, S.; Ueno, M.; Ihara, M. Tetrahedron 2004, 60, 2071–2078. Takasu, K.; Ueno, M.; Inanaga, K.; Ihara, M. J. Org. Chem. 2004, 69, 517–521. Fan Liu, Danica Rankic 5 Myers Chem 115 Cyclobutane Synthesis • Enantioselective [2+2] Cycloadditions with Lewis Acid Catalysts • The reaction is proposed to occur by an asynchronous process. The structures shown below were presented to rationalize the stereochemical outcome: • In early reports, taddolates were found to catalyze formal [2+2] cycloadditions: O N H3CO O O H3CS SCH3 + CO2CH3 TiCl2(Oi-Pr)2 I (10 mol%) 4Å MS, –78 ºC toluene petroleum ether O N H3CS H3CS O O O Ph 96%, 98% ee H3C N B Br3Al O Ph Ph H3C O OH Ph O OH F3CH2CO Ph H3C N B Br3Al O O H H H !+ O O H F3CH2CO H H H Ph Ph I O O O H3CO N O (H3C)3Sn + O SCH3 C H H TiCl2(Oi-Pr)2 I (10 mol%) N H3CO2C O • Transformations of the cyclobutane products: O Sn(CH3)3 SCH3 4Å MS, 0 ºC toluene petroleum ether 93%, 96% ee dr > 20:1 Hayashi, Y.; Narasaka, K. Chem. Lett. 1989, 793–796. Hayashi, Y.; Niihata, S.; Narasaka, K. Chem. Lett. 1990, 2091–2094. OCH2CF3 O OCH2CF3 + II (10 mol%) O H H O OCH2CF3 N Br3Al CH2Cl2, –78 ºC H 87%, 99% ee dr > 99:1 B O + TIPSO OCH2CF3 II (10 mol%) O TBSO CH3 CH3 TBAF, THF 0 " 23 ºC Ph Ph O CH3 O II NaOH, MeOH 23 ºC, 80% (2 steps) CH3 OTIPS 1. CH3ONHCH3•HCl CH3MgBr THF, –30 ºC 2. CH3MgBr, THF –30 " 0 ºC, 85% CH3 • An aluminum bromide oxazaborolidine complex was found to be a highly efficient catalyst: O O TBSO OH O CH3 CH3 O OCH2CF3 CH2Cl2, –78 ºC H Canales, E.; Corey, E. J. J. Am. Chem. Soc. 2007, 129, 12686–12687. 99%, 99% ee dr = 99:1 Canales, E.; Corey, E. J. J. Am. Chem. Soc. 2007, 129, 12686–12687. Fan Liu 6 Myers Chem 115 Cyclobutane Synthesis • Photoredox Catalysis • Cis-olefins are isomerized during the course of the reaction: • Photoredox catalysts absorb light in the visible region and provide a pathway for cyclization mediated by electron transfer rather than direct photoexcitation of the substrate: OCH3 5 mol% Ru(bpy)3(PF6)2 15 mol% MV(PF6)2 Ph MeO Ph H H Ph visible light MgSO4, MeNO2 71%, dr = 6:1 O H3CO O MV2+ = methyl viologen (N,N'-dimethyl-4,4'-bypyridinium) H3C N H3CO Ph visible light MgSO4, MeNO2 88%, dr >10:1 O 5 mol% Ru(bpy)3(PF6)2 15 mol% MV(PF6)2 H H O • Limitation of the method: at least one of the styrenes must bear an electron-donating substituent at the para or ortho position. Aliphatic olefins are not suitable reaction partners. N CH3 • Mechanism: *Ru(bpy)32+ strong reductant visible light • Photoredox catalysis can also be used for [2+2] cycloadditions of enones: N CH3 (MV2+) H3C N Me N +1 e- N Me Ph (MV-radical) Ru(bpy)32+ photocatalyst O O Ph product Ru(bpy)33+ strong oxidant visible light Ru(bpy)3Cl2 (5 mol%) O O H H Ph Ph LiBF4, i-Pr2NEt MeCN, 89%, dr >10:1 MV2+ -1 e- +1 e– OCH3 p-CH3OC6H4 MV-radical Ph OR p-CH3OC6H4 O O Ph H H O O Ph CH3 CH3 visible light Ru(bpy)3Cl2 (5 mol%) LiBF4, i-Pr2NEt MeCN, 84%, dr >10:1 O Ph O CH3 H3C • Upon photoexcitation, the photocatalyst (Ru(bpy)3(PF6)2) acts as a strong reductant, reducing MV by a single electron. • The resulting Ru(III) species acts as a strong oxidant, which oxidizes the electron-rich styrene to produce a radical cation and regenerates photocatalyst. • The resulting radical cation undergoes cyclization. Ischay, M. A.; Lu, Z.; Yoon, T. P. J. Am. Chem. Soc. 2010, 132, 8572–8574. Ischay, M. A.; Anzovino, M.E.; Du, J.; Yoon, T.P. J. Am. Chem. Soc. 2008, 130, 12886–12887. Du, J.; Yoon, T.P. J. Am. Chem. Soc. 2009, 131, 14604–14605. Danica Rankic 7 Myers Chem 115 Cyclobutane Synthesis • Mechanism: • An intramolecular variant was also developed. • The product can be converted to acids, esters, thioesters and amides: visible light *Ru(bpy)3 2+ i-Pr2NEt Li O LiBF4 Ph Ru(bpy)32+ O N i-Pr2NEt +1 e– Ru(bpy)3+ Li –1 e– CH3 O N O visible light Ru(bpy)3Cl2 (2.5 mol%) OBn LiBF4, i-Pr2NEt MeCN, 87%, dr >10:1 O Ph Ph Me CH3 Me O O O H H BnHN CH3 O O N H H H3C N OBn 1. MeOTf, CH2Cl2 67% 2. BnNH2, DBU CH2Cl2, 98% OBn 98%, dr >10:1 Li O O Ph –1 e– CH3 Ph H3C Li O O CH3 H3C Tyson, E. L.; Farney, E. P.; Yoon, T. P. Org. Lett. 2012, 14, 1110–1113. O O Ph CH3 • Styrenes and alkenes undergo [2+2] cycloaddition in the presence of an Ir catalyst (III) and light. The catalyst functions as a photosensitizer. H3C CF3 F • Lewis acid coordination decreases the reduction potential of the enone, facilitating single electron transfer. • Limitation of the method: one coupling partner must be an aromatic ketone. Aliphatic ketones and esters do not under go cycloaddition because of their higher reduction potentials. Ph CH3 visible light III (1 mol%) CH3 CH3 H Ph CH3 H DMSO, 83% O N F OH EtO2C H3C O H3C N N visible light Ru(bpy)3Cl2 (2.5 mol%) O CH3 i-Pr LiBF4, i-Pr2NEt MeCN, 73%, dr >10:1 H3C N O CH3 F N N O F CH3 O CH3 EtO2C DMSO, 86% H3C t-Bu CF3 III H3C CH3 H H • O CH3 O CH3 N i-Pr HO visible light III (1 mol%) PF6– IrIII Ischay, M. A.; Anzovino, M.E.; Du, J.; Yoon, T.P. J. Am. Chem. Soc. 2008, 130, 12886–12887. Du, J.; Yoon, T.P. J. Am. Chem. Soc. 2009, 131, 14604–14605. • !,"-Unsaturated 2-imidazolyl ketones also undergo photochemically induced cycloadditions: t-Bu N HO HO2C H3C H3C CH3 H H • O LiOH 60 ºC 97% CH3 (±)-cannabiorcicyclolic acid Lu, Z.; Yoon, T. P. Angew. Chem. Int. Ed. 2012, 51, 10329–10332 Danica Rankic 8 Myers Chem 115 Cyclobutane Synthesis • Other Methods for Cyclobutane Synthesis • Gold(I)-Catalyzed Ring Expansion of Cyclopropanes • Brook Rearrangement of 1,4-Dicarbonyls • Alkynyl cyclopropanols can undergo ring expansion upon treatment with catalytic Au(I): • Treatment of keto acylsilanes with organolithium reagents produces highly functionalized cyclobutanes favoring cis-stereochemistry between newly formed alcohols t-Bu PhLi, THF i-Pr TBS O O –80 " –30 ºC TBSO Ph OH i-Pr HO Ph 67% HO OTBS [(p-CF3C6H4)3P]AuCl (0.5 mol%) AgSbF6 (0.5 mol%) O CH2Cl2, 23 ºC, 98% i-Pr single isomer 10% Mechanism: • The mechanism is proposed to involve a stereospecific 1,2-alkyl shift: i-Pr TBS O Ph O TBSO Ph i-Pr O TBS O OH i-Pr Ph Li [(p-CF3C6H4)3P]AuCl (1 mol%) AgSbF6 (1 mol%) Ph O TBSO CH2Cl2, 23 ºC, 94% Brook rearrangement H3C H3C CH3 AuL • Ring Expansion of Cyclopropanes via Pinacol-Type Rearrangements TBSO • Hydroxycyclopropyl carbinols can be ring-expanded by treatment with protic or Lewis acids. H3C • Either cis- or trans-substituted cyclobutanones could be produced from a single diastereomer of a an !-hydroxycyclopropyl carbinol: BF3•Et2O (20 mol%) O n-Bu 80% 17:1 cis:trans concerted migration proposed THF, 23 ºC HO Ph CH3 H+ Takeda, K.; Haraguchi, H.; Okamoto, Y. Org. Lett. 2003, 5, 3705–3707. Ph t-Bu p-TsOH•H2O (10 mol%) O CHCl3, 23 ºC Ph Ph AuL O CH3 H3C Ph CH3 Markham, J. P.; Staben, S. T.; Toste, D. F. J. Am. Chem. Soc. 2005, 127, 9708–9709. n-Bu Ph OH single diastereomer n-Bu 94% 1:17 cis:trans thermodynamic product Hussain, M. M.; Li, H.; Hussain, N.; Urena, M.; Carroll, P. J.; Walsh, P. J. J. Am. Chem. Soc. 2009, 131, 6516–6524. Danica Rankic 9 Myers Chem 115 Cyclobutane Synthesis • Cu-catalyzed 1,4-Ring closure • The products can be derivatized: • Homoallylic sulfonates can undergo borylation/cyclization using a CuI catalyst: Bn(H3C)2Si OMs Ph CuCl (5 mol%) dppp (5 mol%) Ph B2pin2, KOt-Bu THF, 23 ºC H3C CH 3 CH3 O B O CH3 O CH3 CH3 CH3 CH3 O B B O O B2pin2 CuCl (5 mol%) dppp (5 mol%) (H3C)2PhSi OMs (H3C)2PhSi H3C H3C H3C H3C H3C CH 3 CH3 O B O CH3 1. TBAF, THF 23 ºC 2. H2O2, KHCO3 CH3OH, 23 ºC OBz 49% (2 steps) (dppp)Cu (dppp)CuI-Bpin R2 OBz Bpin H R1 OMs +KOt-Bu Bpin HO OMs (dppp)CuIOt-Bu R1 OBz R1 pinB Ot-Bu pinB!Bpin OBz HO 1. TBAF, THF 23 ºC 2. H2O2, KHCO3 CH3OH, 23 ºC 57% (2 steps) R2 R2 Bn(H3C)2Si 2. PhCOCl, C5H5N CH2Cl2, 0 ºC 61% (2 steps) 1. LiCH2Cl, THF –78 " 23 ºC 2. H2O2, NaOH THF, 0 ºC 3. PhCOCl, C5H5N CH2Cl2, 0 ºC 73% (3 steps) R3Si 1. H2O2, NaOH THF, 0 ºC B2pin2, KOt-Bu THF, 23 ºC • Mechanism: CuCl BPin R2 R1 R2 Bpin H tBuO CuIII dppp R1 t-BuO K+ CuI dppp Bpin Ph BPin 1. BCl3, CH2Cl2 23 ºC Ph NHBn 2. BnN3, CH2Cl2 0 ºC, 57% • Note that in each case the stereochemistry of the starting material is preserved in the product. H OMs KOMs • Limitation of the method: only aryl- or silyl-substituted olefins react; alkyl olefins do not undergo borocupration. Ito, H.; Toyoda, T.; Sawamura, M. J. Am. Chem. Soc. 2010, 132, 5990–5992. Markham, J. P.; Staben, S. T.; Toste, D. F. J. Am. Chem. Soc. 2005, 127, 9708–9709. Danica Rankic 10
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