Strain-Promoted Reactivity in Organic Synthesis Steph McCabe Frontiers of Chemistry 08/19/2017 Wipf Group 1 Steph McCabe @Wipf Group Page 1 of 30 09/02/2017 2/10/2011 4.4 Conformations of Cycloalkanes Cyclopropane • Most strained of all the rings • Angle strain – caused by 60º C-C-C bond angles • Torsional strain – caused by the eclipsed C-H bonds on neighboring carbon atoms a) Structure of cyclopropane showing the eclipsing of neighboring C- H bonds giving rise to torsional strain b) Newman projection along a C-C bond of cyclopropane Conformations of Cycloalkanes • Bent C-C bonds • Orbitals can’t point directly toward each other • Orbitals overlap at a slight angle • Bonds are weaker and more reactive than typical alkane bonds 2/10/20112/10/2011 • C-C bond: 4.4 Conformations255 kJ/mol (61 kcal/mol) of Cycloalkanes for cyclopropane What 4.4is ConformationsRing355 kJ/mol Strain? (85 ofkcal/mol) Cycloalkanes for open-chain propane Cyclopropane Cyclopropane• Most strained of all the rings Ring Strain Theory: Adolf von Baeyer• • (NobelMostAngle strained strain Prize of – allcaused in the Chemistry rings by 60º C-C- C1905) bond angles 1. Angle Strain: Expansion/compression• • AngleTorsional of strain ideal strain– caused(tetrahedral) – caused by 60 ºby C -the Cbond-C eclipsed bond angle angles C-H bonds on neighboring • Torsionalcarbon strainatoms – caused by the eclipsed C-H bonds on neighboring 2. Torsional Strain: Rotational strain e.g.carbon a)eclipsingStructure atoms bonds of cyclopropane on neighboring showing the eclipsing atoms of vs neighboring staggered C- 3. Steric Strain: Repulsive interaction whena) Structure atomsH bonds of giving approachcyclopropane rise to torsionaleach showing other strain the eclipsing too closely of neighboring C- b)H bondsNewman giving projection rise to alongtorsional a C strain-C bond of cyclopropane b) Newman projection along a C-C bond of cyclopropane Conformations of Cycloalkanes Cyclobutane • Total strain is nearly same as cyclopropane • Angle strain – less than cyclopropane • Torsional strain – more than cyclopropane because of larger number of ringRing hydrogens strain: 27.5 kcal/mol ΔH"(strain)" • Not planar (not flat) ∠ (kcal/mol)" C–C–C 60° • One carbon atomC- liesC 25bond:º above 61 the kcal/mol plane of the(vs other85 kcal/mol three in • Newman projection along C1-C2 bond shows that neighboring C-H bonds are not quitepropane) eclipsed Conformations of Cycloalkanes mainly"angle" mainly"transannular"strain" strain" Conformations• Bent C-C bonds of Cycloalkanes • Orbitals can’t point directly toward each other • Bent C-C bonds 1" • Orbitals overlap at a slight angle • Orbitals can’t point directly toward each other • Bonds are weaker and more reactive than typical alkane bonds C–C–C ∠109.5° • Orbitals overlap at a Ringslight Strain:angle 26.4 kcal/mol • Bonds are weaker andC–C– moreC reactive∠~88 °than typical alkane bonds C-C bond: 63 kcal/mol (vs 85 kcal/mol in butane) 2 Steph McCabe @Wipf Group Page 2 of 30 09/02/2017 2 • C-C bond: 255 kJ/mol (61 kcal/mol) for cyclopropane • C-C bond: 355 kJ/mol (85 kcal/mol) for open-chain propane 255 kJ/mol (61 kcal/mol) for cyclopropane 355 kJ/mol (85 kcal/mol) for open-chain propane Conformations of Cycloalkanes ConformationsCyclobutane of Cycloalkanes • Total strain is nearly same as cyclopropane Cyclobutane• Angle strain – less than cyclopropane • Total strain• Torsional is nearly strain same – asmore cyclopropane than cyclopropane because of larger number of ring hydrogens • Angle strain – less than cyclopropane • Not planar (not flat) • Torsional strain – more than cyclopropane because of larger • One carbon atom lies 25º above the plane of the other three number of ring hydrogens • Newman projection along C1-C2 bond shows that neighboring C-H • Not planarbonds (not are flat) not quite eclipsed • One carbon atom lies 25º above the plane of the other three • Newman projection along C1-C2 bond shows that neighboring C-H bonds are not quite eclipsed 2 2 Small Strained Aza- and Carbocycles X cyclopropane cyclopropene methylenecyclopropane vinylcyclopropane bicyclo[1.1.0]butane bicyclo[1.1.1] pentane [1.1.1]propellane N N N N N N H H NH aziridine 2H-azirine methylene aziridine N-vinylaziridine 1-azabicyclo[1.1.0]butane 1-azabicyclo[1.1.1]pentane 2-aza[1.1.1]propellane H *unknown NH HN N N H 1H-azirine 2-vinylaziridine 2-azabicyclo[1.1.0]butane 2-azabicyclo[1.1.1]pentane *unknown *unknown cyclobutane cyclobutene methylenecyclobutane bicyclo[2.2.0]hexane bicyclo[2.1.0]pentane ‘housane’ NH N N NH N azetidine 1-azetine 2-methyleneazetidine 1-azabicyclo[2.2.0]hexane 1-azabicyclo[2.1.0]pentane *unknown NH HN NH N NH H 2-azetine 3-methyleneazetidine 2-azabicyclo[2.2.0]hexane 2-azabicyclo[2.1.0]pentane 5-azabicyclo[2.1.0]pentane § Cyclopropane (~27 000 hits in scifinder) vs bicyclobutane (831), methyleneaziridine (89), azabicyclobutane (56) 3 Steph McCabe @Wipf Group Page 3 of 30 09/02/2017 Scope/Brief History Scope of Presentation: 1. Reactivity/applications of underrepresented carbo- and azacycles containing a 3-membered ring 2. Proposal Section – Gaps in the synthesis and reactivity profile of strained ring systems and applications in total synthesis N H N methylene aziridine bicyclo[1.1.0]butane 1-azabicyclo[1.1.0]butane (MA) (BCB) (ABB) 1950s – 1990s 2001-2017 2008-2017 Theoretical/Synthetic Research General reactivity Applications § Useful models § Methods to form § Total synthesis to study ring strain small-medium § Chiral Ligands for in organic compounds sized rings and asymmetric catalysis § Synthesis: novel scaffolds § Medicinal chemistry MA (1951, Pollard) unnatural amino acids, peptide BCB (1959, Wiberg) labeling ABB (1969 Funke) 4 Steph McCabe @Wipf Group Page 4 of 30 09/02/2017 Ring Strain Energies of [ 31 Radialenes The Journal of Physical Chemistry, Vol. 97, No. 19, 1993 4997 7038 J. INCE et aL 1.3116 c 3.0 1.5270 13079 1.4212 160.7 H 1.4622 c Our initial investigations focused on the preparation of N-benzyl substituted rncthyleneaziridines. This decisionH was made on the basis of the known stability of the N-benzyl group to a wide range of reaction conditions and the ease withH which the bcnzylic C-N bond can be cleaved by hydrogenation.8 Thus, three 3 04 related methylcneazin'dine precursors 5-7 were made differing only in the nature of the substituents attached to the benzylic carbon atom. Amine precursors 5 and 6 were prepared by alkylation of benzylamine and (S)- 1- phenylethylamine respectively with commercially available 2,3-dibromopropene. While the N-trityl derivative 7 could not be prepared in this way using the more sterically encumbered triphenylmethylamine, an alternative approach involving coupling of N-(2-bromoallyl)-amine4 9 and trityl chloride readily furnished this precursor in good yield (Scheme 2). PtT/~NH2 i 1.3120 x"~ R~,~Ph 5 (R,, R2 = H); M~.,N~AO,, ii =, NH 6 (R"1 = H, FI2 = Me); 5 P H2 l 7 (R1, R2 = Ph) Br A;H 2 iii f d 5pl 6 Methyleneaziridines:4 Properties Scheme 2. Reagents & Co~li#ons: (i) 2,3-dibrompmpene,K2CO3, THF, reflux, 68% (5); (ii) 2,3-dibmmol~pene, K2CO3, Et20, reflux, 76% (6); (iii) Ph3CCI, Et3N, 121-121212,88% (7). § Ring strain ~43 kcal/molWith the requisite precursors in hand, we were ready to examine the conversion of these materials into the Ring Strain Energy (HF/6-31G*) corresponding methyleneaziridines employing the procedure described by Pollard and Parcell.1 Treatment of the N-benzyl1.4073 derivative 5 with differing amounts of sodium amide (1.1-15 equiv) for varying reaction times (5- 120 rain) lead to the formation of complex mixtures of products from which no appreciable quantifies of the desired methyleneaziridine could be isolated. Since closely related compounds such as N-ethyl N methyleneaziridine canN be made using this chemistry, we reasoned that the increased acidity of the hydrogens on H the benzylic carbon atomH may be causing the deu'imental side reactions. To test this hypothesis, we next chose to examine the cyclisation of N-trityl derivative 7 which has no such acidic hydrogens. In this instance, we 29.71 kcal/molwere delighted to 42.55discover thatkcal/mol treatment of this 28.75substrate withkcal/mol 15 equivalents of sodium40.03 amide kcal/mol in liquid ammonia for 6 hours smoothly lead to the formation of desired methyleneaziridine 8 in 72% yield (Scheme 3). The structure of this compound was unambiguously established using x-ray crystallography. While Quast et al § Very little enamine havecharacter published an x-ray(Nitrogen crystallographic lone study of pair 1-(1-adamantyl)-2-isopropylidineazin'dine, is pyramidal) l0 we believe this represents the first crystallographic study of a simple methyleneaziridine.11 Ph~Ph 3 NaNH2, NHa =.. Ph~Ph 9 72% N ? Ph 8 Ph Scheme 3 Ph X-Ray CrystalStructure of N-(a'ipbcnylm¢~yl)-2- methyleneaziridine8 § Thermal decomposition to olefin and isonitrile (slow T>120 °C, fast T>190 °C) N + CNR R Calculated ring strain energy (HF/6-31G*)2.0 Bachrach J. Phys. Chem. 1993, 97, 4996; Shipman Tetrahedron, 1996, 52, 7037 3.9 A"....." A"....." 1.4652 1.4682 5 Steph McCabe @Wipf Group d Page 5 of 30 09/02/2017 Figure 1. Optimized geometries of the radialenes and lower homologs. The HF/6-31GS geometries are listed above the MP2/6-31G* results. All distances are in A and all angles are in deg. initio calculations of aza[ 31 radialene (5) and phospha [3]radialene structures are drawn in Figure 1 and the energies are listed in (6). In order to address the trends in ring strain energy due to Table I.