Intramolecular Cyclopropanations.Pptx

Nicholas Tappin Topic Review Renaud Group January 28th 2016 Universität Bern Intramolecular Cyclopropanaons

Me CO2Me O cat. Cu(TBSA)2 CO Me O O 2 O H DCM, 70 °C, 8 h H N2 60%

Cl Cl Me LiCl, CSA O NC DMF, 140 °C O H

71% NH (–)-hapalindole G

Example of ulity of intramolecular cyclopropanons: Fukuyama, T.; Chen, X. J. Am. Chem. Soc. 1994, 116, 3125–3126. 1 A quick note on bonding

“Ring strain confers exceponal reacvity to the cyclopropane ring.” Chimia, 2009, 63, 162-167. And many publicaons from a synthec organic chemists concerning the synthesis and reacvity of cyclopropanes has a similar phrase!

2 How do you explain the following observation?

OR E E ROH E R R R no ring strain Markovnikov

E E depending on ring strain: substitution 27.5 kcal mol−1 R R pattern

E ring strain: no reaction 26.5 kcal mol−1 R

c.f. C–C bond dissociation energy is ∼83-85 kcal mol−1

Ring strain might provide a strong thermodynamic driving force for reacon but is doesn’t explain the reacvity. A suitable answer must therefore invoke bonding.

3 Problem: tightest angle between any AOs is 90° (e.g. orthogonal p-orbitals) but in cyclopropane we have to accomodate a bond angle of 60°

Pauling τ-bond treatment Hückel σ/π-bond treatment

Ψ(E',a) Ψ(E',b)

Ψ(A2')

Ψ(E',c) Ψ(E',d)

Ψ(A1') 22° and ~20% less effective overlap

Coulson-Moffit orbitals: Walsh orbitals: 2 sp3-hybridized C AOs orbitals sp -hybridized C AOs N.B.: This model is generally accepted (as is Hückel's approach to bonding) but it is likely wrong as it may not represent the ground state: Specifically, relative energies of Ψ(A2') with Ψ(E',a) and Ψ(E',b) are switched when valence AOs are used as the basis set instead of methylene and choosing methylene as basis set removes C–H bonds from MO picture See [Wiberg, K. B. Acc. Chem. Res. 1996, 29, 229–234] and [reference 17 therein]. Walsh orbitals work in other cases outside of cyclopropane.

X-ray diffraction of cis-1,2,3-tricyanocyclopropane: Hartman, A.; Hirshfeld, F. L. Acta Crystallographica 1966, 20 (1), 80–82.

5 Classiﬁcations in a Venn diagram

Cyclopropanations

Intramolecular Intermolecular Cyclopropanations Cyclopropanations S P S I P all C atoms in product come from substrate: 'substrate-based' cyclopropanation

S1 + S2 I P S + S P C atoms in product come from two educts 1 2 (but reaction occurs via an intermediate, i.e. C atoms in product overall still intermolecular cyclopropanation come from two educts even if the cyclopropanation step is itself mechanistically intramolecular)

6 Classiﬁcations in a Venn diagram

Cyclopropanations

Intermolecular Intramolecular Cyclopropanations Cyclopropanations S P S I P all C atoms in product come from substrate: 'substrate-based' cyclopropanation

S1 + S2 P1 P2

7 Examples from free carbene chemistry

Intermolecular cyclopropanation example (no intermediate)

S1 + S2 P

Br Br BrBr Me t-BuOK Br Br + Me + Me CHBr3 Me singlet carbene Me Me Me 70% yield <1% trans Me

8 Examples from free carbene chemistry

Intermolecular cyclopropanation example (via an intermediate)

S + S I P 1 2 65% cis 35% trans N2 Me Me Me Me hν Me + Me + triplet carbene

hν Me Me Me Me

spin-flip spin-flip slow slow Me Me rds Me Me bond rotation

fast triplet diradical intermediate

9 Examples from free carbene chemistry

Intramolecular cyclopropanation example

S P or S I P

Li H H n-BuLi -elimination t-BuOK α CH C—H insertion RO RO Cl RO RO Cl Me Me Me Me Me Me H H H

10 Ambiguous examples from free carbene chemistry and another, unambiguous (?), example

S1 + S2 I P

O NMe4 1) t-BuCOCl (CO) Cr 5 (CO) Cr Ph 2) (CO)4Cr O 4 O O Ph Ph Ph OH unstable – CO for homoallylic alcohols

S1 + S2 P1 P2

COCl O Ph Ph Bn O NMe Bn O H O H 4 O (CO) Cr O O Cr(CO) 5 Bn Cr(CO)4 Bn 4 H Ph DCM, –10 °C to r.t., 2 h, – CO partially stable Ph at –10 °C

Intramolecular cyclopropanation example via an isolable first product arrived at from an intermolecular process

S1 + S2 P1 P2

Cl R ATRA Cl Cl 1,3-dechlorination R Ph + Cl Ph R Ph 11 Intramolecular cyclopropanation: 1,3-cyclization

cyclopropane cyclization occurs with formation of 1 C—C σ-bond

elimination products

X Y – MX and MY or zwitterionic break 2 R – XY synthon σ-bonds

R break 1 π-bond and 1 σ-bond X Y X Y R or or – MY R R R diradical break 2 synthon π-bonds X Y X Y or none R R

Kulinkovich, O. G. Cyclopropanes in organic synthesis. (Hoboken, New Jersey: Wiley, 2015), 57-58. 12 Intramolecular cyclopropanation: [2+1] and insertion reactions

cyclopropane cyclization occurs with formation of 2 C—C σ-bonds (except insertion reactions)

carbene CH HC CH 2 addn

H carbene Chemoselectivity CH2 C—H insern issuses (e.g. solvent)

H2C CH2 carbene c.f. cyclobutane H C CH 2 CH 3 C—C insern chemistry, 2 other types difficult 1,1-carbodianion and CH2 HC CH2 1,2-carbodication Mostly intermolecular 1,1-carbodication CH HC CH and 2 2 1,2-carbodianion

or involving recombination of respective radical-ion species

Kulinkovich, O. G. Cyclopropanes in organic synthesis. (Hoboken, New Jersey: Wiley, 2015), 65. 13 Cyclopropane formation from reactions to cyclopropene (without cyclopropane cyclization)

cycloadditions

additions E Nu

will not be covered in this topic review

For some informaon, however, on this topic see: Kulinkovich, O. G. Cyclopropanes in organic synthesis. (Hoboken, New Jersey: Wiley, 2015), 88-90. 14 1,3-cyclizations by breaking 2 σ-bonds

cyclopropane cyclization occurs with formation of 1 C—C σ-bond

elimination products

X Y – MX and MY or zwitterionic break 2 R – XY synthon σ-bonds

R break 1 π-bond and 1 σ-bond X Y X Y R or or – MY R R R diradical break 2 synthon π-bonds X Y X Y or none R R

15 1,3-dehalogenation: dissolving metal

Br Na Often attributed as first Freund, A. J. Prakt. Chem., cyclopropane synthesis Br 1882, 26, 367–377.

Br Br Unique p-character of 2 bonding in cyclopropanes Br H2O

Cl Mg Cl2 Cl Cl 17% 34% Gragson, J. T.; Greenlee, K. W.; Derfer, J. M.; Boord, C. E. J. Am. Chem. Soc. 1953, 75, 3344–3347.

Na/ NH3(l), t-BuOH Cl THF, 65 °C 43% multigram Salaun, J. R.; Champion, J.; Conia, J. M. Org. Synth. 1977, 57, 36.

16 1,3-dehalogenation: dissolving metal

ruthenium-catalyzed Kharash ATRA/ 1,3-dehalogenation 1-pot sequence

ATRA Cl X 1,3-halogenation X R R + III R' Ru R' R Mg R' Cl Mg RuII

[Cp*RuCl (PPh )] 2 3 Cl Cl THF (1 mol%) CO2Et Cl CO2Et Ph + 0 C , 1 h neat, Mg, 60 °C, 6 h Ph CO2Et ° Ph 74% Cl d.r. = 1:3 Thommes, K.; Kiefer, G.; Scopelliti, R.; Severin, K. Angew. Chem. Int. Ed. 2009, 48, 8115–8119.

[Cp*RuCl (PPh )] Br 2 3 Br Cl THF Ph Ph + (1 mol%) CF Cl CF3 neat, Mg, r.t., 2 h Ph CF3 –78 °C to r.t., 1 h 3 55% d.r. = 27:1

Br [Cp*RuCl (PPh )] 2 3 Br Cl THF n-oct n-oct + (2 mol%) Cl CF CF 3 neat, Mg, r.t., 15 h n-oct CF3 –78 °C to r.t., 1 h 3 46% d.r. = 1.1:1 Risse, J.; Fernández-Zúmel, M. A.; Cudré, Y. Org. Lett. 2012, 14, 3060–3063. 17 elimination of HX

ONa O O H O/ H+ NaOH(aq), boiling 2 Cl work-up

77–83% ONa Cl O ONa E2 ONa Cl

O O ONa

Cannon, G. W.; Ellis, R. C.; Leal, J. R. Org. Synth. 1951, 31, 74.

18 Double Tsuji-Trost by palladium-catalyzed allylation and palladium-catalyzed cyclopropanation

method A, CN AcO CN CO2Et Genet, J.-P.; Piau, F. J. Org. Chem. 1981, 46, 2414–2417. or CO Et H CO2Et + 2 method B H CN

Method A: NaH only 0 °C then 65°C: d.r. = 1:1; Y = 75% Method B: NaH, 0 °C then Pd0 65°C : d.r. = 19:1; Y = 70%

- Tsuji-Trost type mechanism for first allylation and then second, except when no palladium used. For origin of this discovery: Colobert, F.; Genet, J.- P. Tetrahedron Lett. 1985, 26, 2779–2782 and reference [6] therein.

DBU (1.1eq) ArCOCl = CO2Me PhO2S CO2Me ArCOCl Cl Cl R' OAc SO2Ph OH then 2.5 mol% R' Cl Pd(dppe)2 OH O

attack from above

CO Me R' ∗ CO2Me NaH, 0 °C; R' CO Me T-T SN2' 2 2 R' ∗ SO Ar OCOAr SO2Ph 5–10 mol% SO2Ar 2 PdLn Pd(dppe)2 PdLn

19 ‘Regio-incorrect Tsuji-Trost’ leads to isolable palladocyclobutane

L R MeO2C Pd L MeO C Cl MeO C 2 + Pd 2 2

isolated and characterized: R = H 70% Hoffmann, H. M. R.; Otte, A. R.; Wilde, R = Me 78% A.; Menzer, S.; Williams, D. J. Angew. R= CO Me 37% Chem. Int. Ed. Engl. 1995, 34, 100–102. 2

Cl Pd 2 MeO2C CO2Me MeO2C CO2Me NEt3, HMPA THF, −78 °C

- Need appropiate enolate ester: Hegedus, L. S.; Darlington, W. H.; Russell, C. E. J. Org. Chem. 1980, 45, 5193–5196.

- Although Hückel calculations suggested attack at central carbon in π-allyl complex would be unfeasible [Curtis, M. D.; Eisenstein, O. Organometallics 1984, 3, 887–895], here it does occur.

- Nuc attack on η3-allyl palladium complexes is explored further: Aranyos, A.; Szabó, K. J.; Castaño, A. M.; Bäckvall, J.-E. Organometallics 1997, 16, 1058–1064.

Hegedus, L. S.; Söderberg, B. C. G. Transion metals in the synthesis of complex organic molecules, 3rd Ed. (Sausalito, California: University Science Books, 2010), 28-29. 20 elimination of HX: enantioselective

Enantioselective (here with proline enamine organocatalysis)

(20 mol%) Me OHC N CO2H CO2Et OHC I H EtO C CO Et NEt (1.0 eq) CO2Et 2 2 3 70% mes, –15 °C, 216 h 93:7 er

N.B.: - this was only example for cyclopropane, others were for cyclopentanes - long reaction times, higher catalyst loading (c.f. 24 h with 10 mol%) (10 mol%) Me CO H I N 2 H OHC OHC NEt3 (1.0 eq) EtO C CO Et EtO2C CO2Et CHCl3, –30 °C, 24 h 2 2 92% 97.5:2.5 er Vignola, N.; List, B. J. Am. Chem. Soc. 2004, 126, 450–451.

21 γ-chloropropylborane-ate complex

β-chloroethyl

HO OH Cl OMe2 H2O 2 B B B(OH)3 + HCl + Cl HO Cl Cl

γ-chloropropyl OH OH B B B(OH)Me2 + HCl + Cl Cl

Discovery: Hawthorne, M. F.; Dupont, J. A. J. Am. Chem. Soc. 1958, 80, 5830–5832.

Y (%) R δ-chlorobutyl Cl 1) B H 2 6 H 43 Cl B2H6 Cl Me 71 2) MOH R R n-propyl 61 BR 100 °C, Ph 55 2 12 h Bn 45

Hawthorne, M. F. J. Am. Chem. Soc. 1960, 82, 1886–1888. Problem: allylchloride powerfully directive (overides inherent selectivity of borane during hydroboration)

OH R2B Cl B2H6 Cl ~1:1 Cl OH

BR2 22 γ-chloropropylborane-ate complex

Sia OH Sia OH disiamylborane B B Sia Cl slow Sia Cl coordination poor scope, B side rxns when H chloride is reactive

Ph Me Me 1) 9-BBN 1) 9-BBN Cl Me Ph Me 2) NaOH 2) NaOH 85% 92% Ph Cl 1) 9-BBN Cl 92% Cl 1) 9-BBN 2) NaOH Ph 75% Ph 2) NaOH 1) 9-BBN 91% Cl Cl Cl 2) NaOH Cl 75%

Cl 1) 9-BBN Cl + no cyclobutane Cl 2) NaOH 81% Cl 0%

Brown, H. C.; Rhodes, S. P. J. Am. Chem. Soc. 1969, 91 (8), 2149−2150.

23 1,3-cyclizations by breaking 1 σ-bond and 1 π-bond

cyclopropane cyclization occurs with formation of 1 C—C σ-bond

elimination products

X Y – MX and MY or zwitterionic break 2 R – XY synthon σ-bonds

R break 1 π-bond and 1 σ-bond X Y X Y R or or – MY R R R diradical break 2 synthon π-bonds X Y X Y or none R R

24 Diastereoselective with chiral aux

Diastereoselective (here with chiral auxilary) R* = (–)-8-phenylmenthyl (–)-8-phenylmenthol I CO2R* Ti(O-t-Bu)4 (1.0 eq) HO CO2R* I2 (4.0 eq), pyr (2.0 eq), CO2R* CO2R* Ph MeCN, 0 °C, 20 h 89% 30:1 er

RO OR Ti O O Ph highly organized Ti-enolate leads O O to diastereoselective iodoination Ph

Inoue, T.; Kitagawa, O.; Ochiai, O.; Taguchi, T. Tetrahedron: Asymmetry 1995, 6, 691–692. Chiral titanium complex failed to induce enantioselectivity: Kitagawa, O.; Taguchi, T. Synlett 1999, 1191–1199.

25 1,3-cyclizations by breaking 2 π-bonds

cyclopropane cyclization occurs with formation of 1 C—C σ-bond

elimination products

X Y – MX and MY or zwitterionic break 2 R – XY synthon σ-bonds

R break 1 π-bond and 1 σ-bond X Y X Y R or or – MY R R R diradical break 2 synthon π-bonds X Y X Y or none R R

26 Photolysis of double bonds

O O OH NEt3 hν Ph Ph Ph 77% Ph HO

NEt3 H2O

NEt3 NEt2 NEt3 NEt2 NEt3 O O O O Ph Ph Ph Ph Ph Ph O HO Hasegawa, E.; Katagi, H.; Nakagawa, D.; Horaguchi, T. Tetrahedron Lett. 1995, 36, 6915.

hν + 85%, 30g scale

hν

Wilzbach, K. E.; Kaplan, L. J. Am. Chem. Soc. 1966, 88, 2066–2067. 27 Intramolecular cyclopropanation: [2+1] and insertion reactions

cyclopropane cyclization occurs with formation of 2 C—C σ-bonds (except insertion reactions)

carbene CH HC CH 2 addn

H carbene Chemoselectivity CH2 C—H insern issuses (e.g. solvent)

or involving recombination of respective radical-ion species

Kulinkovich, O. G. Cyclopropanes in organic synthesis. (Hoboken, New Jersey: Wiley, 2015), 65. 28 1,1-carbodication and 1,2-carbodianion

29 Kulinkovich-de Meijere hydroxycyclopropanation: intermolecular version and mechanism O Ti(O-i-Pr)4, c-hexMgCl + OH OMe 95% cis:trans > 98:2 Mechanism reductive EtMgX (2 eq) i-Pr-O β-H-elimination i-Pr-O elimination i-Pr-O TiCl(O-i-Pr)3 or Ti(O-i-Pr)4 Ti H Ti Ti (5−10 mol%) i-Pr-O i-Pr-O H i-Pr-O EtH O i-Pr-O EtH Ti R OR' i-Pr-O

i-Pr-O i-Pr-O Ti Ti i-Pr-O i-Pr-O O OR' R

R R'OMgX + R i-Pr-O O OMgX Ti i-Pr-O OR' 2 EtMgX (a) For a review: Kulinkovich, O. G.; de Meijere, A. Chem. Rev. 2000, 100, 2789−2834. (b) For an important applicaon to total synthesis: Kingsbury, J. S.; Corey, E. J. J. Am. Chem. Soc. 2005, 127, 13813−13815. (c) Hegedus, L. S.; Söderberg, B. C. G. Transion metals in the synthesis of complex organic molecules, 3rd Ed. (Sausalito, California: University Science Books, 2010), 142-143. 30 Kulinkovich-de Meijere reaction: intramolecular version and intelligent modiﬁcation

A variation allows exhange of alkene component by exploiting the reversibility of the titanacyclopropane formation to increase substitution on the resulting cyclopropane. This also can open posibilities for intramolecular cyclopropanation: Lee, J.; Kim, H.; Cha, J. K. J. Am. Chem. Soc. 1996, 118 , 4198−4199. The exchange may be encouraged by choice of Grignard reagent: R i-Pr-O R i-Pr-O c-hexMgCl + Ti(O-i-Pr)4 Ti Ti i-Pr-O i-Pr-O c-hexane

Analogously, intramolecular reaction of enamides to cyclopropylamines H c-pent-MgCl c-pent-MgCl O H O TiCl(O-i-Pr)3 TiCl(O-i-Pr)3 NEt2 N PhN NEt2 Ph THF, rt THF, rt 93% 64% Lee, J.; Cha, J. K. J. Org. Chem. 1997, 62, 1584−1585.

31 Kulinkovich-de Meijere reaction: intramolecular version and intelligent modiﬁcation

O 5-exo-trig i-Pr-O i-Pr-O OMe Ti Ti i-Pr-O i-Pr-O O CO2Me OMe 3 O H OH i-Pr-O OMe 6-exo-trig cat. cycle i-Pr-O Ti i-Pr-O Ti i-Pr-O Ti i-Pr-O i-Pr-O O OMe 1,2 H R [Ti] O O cat. cycle OH OCOR i-Pr-O O O 2 Ti R i-Pr-O H R OH

See also: Kasatkin, A.; Sato, F. Tetrahedron Lett. 1995, 36, 6079–6082.

32 carbene [2+1] reactions (and 2 insertion examples)

33 Electrophilic group 6 Fischer carbenes

O NMe4 1) t-BuCOCl (CO) Cr 5 (CO) Cr Ph 2) (CO)4Cr O 4 O O Ph Ph Ph OH unstable – CO 83% for homoallylic also pyrans and pyrrolidines alcohols Söderberg, B. C.; Hegedus, L. S. Organometallics 1990, 9, 3113–3121.

Facile synthesis of Fischer carbenes using gropu 6 metals 'mixed anhydride' O O RLi Me4NBr O t-BuCOCl Cr(CO)6 (CO) Cr NMe4 O 5 Li (CO) Cr R 5 slow, –40 °C (CO)5Cr t-Bu R R

OLi (CO) Cr 5 reactive species R (vacant site in TM complex) R'OH OR' – CO OR' (CO) Cr + t-BuCO H (CO) Cr fast, –20 °C 5 2 4 R R Semmelhack, M. F.; Bozell, J. J. Tetrahedron Lett. 1982, 23, 2931–2934. Hegedus, L. S.; Söderberg, B. C. G. Transion metals in the synthesis of complex organic molecules, 3rd Ed. (Sausalito, California: University Science Books, 2010), 196-199. See also 183-187 for background informaon on these complexes. 34 Electrophilic group 6 Fischer carbenes mechanism – CO OMe heat OMe X OMe (CO)5Cr (CO)4Cr (CO)4Cr pressure Ph Ph Ph OMe + CO X Ph X OMe OMe (CO)5Cr (CO) Cr 100 atm CO 4 Ph Ph metathesis and reductive cyclopropanation OMe elimination Ph suppressed (CO)4Cr H H OMe X H (CO) Cr Ph Ph X 4 β-hydride elimination reductive H OMe elimination X evidence for metallacyclobutane: alkene metathesis Ph OMe – CO OMe OR OMe (CO)4Cr (CO)5Cr + OR (CO)4Cr + Ph 80 °C H Ph RO

heteroatom-stabilized whereas: chromium carbene Ph Z OMe OMe (CO)4Cr OR OR Ph (CO)5Cr (CO)5Cr Z 50–90% H H Z = CO Me, CONMe , CN, P(O)(OMe) , SO Ph 2 2 2 2 35 Electrophilic group 6 Fischer carbenes

Diastereoselectivity from a leaving chiral auxilary. When alkene tethered in proximity may have metathesis.

OLi OMe Ph O 1) Et O, –30 C, or OBIPC2 2 ° (–)-sparteine solvent (CO) W + 5 (CO) W Ph (–)-BIPC-Cl 5 2) MeOTf, 0 °C 45% (55%) ee = 40% (55%) BCl H

MgBr (CO) W O 5 O 2 THF, 90 °C Et2O, –50 °C H H Ph 75% Ph 64% Barluenga, J.; Diéguez, A.; Rodríguez, F.; Flórez, J.; Fañanás, F. J. J. Am. Chem. Soc. 2002, 124, 9056–9057.

Ph Ph COCl O O H O H O O Bn Bn M Bn M O Bn NMe4 O (CO) Cr H Ph Ph 5 DCM, –10 °C O H O H Ph to r.t., 2 h Ph O M O 73% Bn Bn 1 diastereoisomer Barluenga, J.; Aznar, F.; Gutiérrez, I.; Martín, J. A. Org. Lett. 2002, 4, 2719–2722.

36 Electrophilic group 6 Fischer carbenes not a cyclopropanation rxn, but via a cyclopropane intermediate H COCl O O NMe4 (CO) Cr O 5 DCM, –10 °C to r.t., 2 h Ph 63% Ph Cope rearragement of divinyl cyclopropane via aromatic TS??? H H H

O [2+2] O red. elim. O (CO) Cr (CO) Cr 4 O 4 O O

Ph Ph Ph Barluenga, J.; Aznar, F.; Gutiérrez, I.; Martín, J. A. Org. Lett. 2002, 4, 2719–2722.

OMe SiO2, EtOAc H + O (CO)5Cr O 63 °C, 3 h, Soxhlet O 85% enol no longer conjugated with carbene

Cr(CO) Cr(CO) (CO) Cr OMe 4 4 H 4 O OMe H OMe O O fast carbene-alkyne O metathesis OMe 37 Electrophilic group 6 Fischer carbenes

CO Et CO Et Bu 2 2 OMe Bu (CO) Mo 5 Bu OMe OMe EtO2C H + H PhH, 60 °C, 0.5 h [2+2]-metathesis 1:4.8 87% Bu Cope [3,3]-sigmatropic OMe (CO)4Mo or a EtO C CO2Et 6-π electrocyclization??? 2 c.f. T, t EtO2C EtO2C retro-[2+2] Mo(CO)4 [2+2] red. elim. Bu H Mo(CO)4 H OMe

Bu MeO Bu MeO Harvey, D. F.; Lund, K. P. J. Am. Chem. Soc. 1991, 113 , 5066–5068; Harvey, D. F.; Brown, M. F. J. Org. Chem. 1992, 57, 5559–5561. For examples with ene-yne, i.e. not diene where there is no Cope rearrangement: Harvey, D. F.; Lund, K. P.; Neil, D. A. J. Am. Chem. Soc. 1992, 114 , 8424–8434.

38 Rh- and Cu-carbenes with α-diazocarbonyl compounds: mechanism

Evidence for Cu- and Rh-bound carbenes from catalytic decomposition of α-diazocarbonyl compounds 1) metathesis: highly efficient transformations that can be easily explained with metallacycobutane species and not by other types of carbenoid species

O O cycloaddns cat. Rh2(OAc)4 N 2 DCM, 25 °C 95%!

carbene Ox. Red. Elimn formn addn O O O O retro- [2+2] [2+2] [2+2] RhL RhLn n RhLn RhLn

Padwa, A.; Austin, D. J.; Xu, S. L. Tetrahedron Lett. 1991, 32, 4103–4106; Hoye, T. R.; Dinsmore, C. J. Tetrahedron Lett. 1991, 32, 3755–3758; Hoye, T. R.; Dinsmore, C. J. J. Am. Chem. Soc. 1991, 113 , 4343– 4345; Padwa, A.; Austin, D. J.; Xu, S. L. J. Org. Chem. 1992, 57, 1330–1331.

39 Rh- and Cu-carbenes with α-diazocarbonyl compounds: mechanism

2) enantioselectivity: achiral substrates transformed into entioenriched products by catalytic quantities of enantiopure ligands and an appropiate metal

H cis:trans = 99:1 N Rh2(4S-MACIM)4 (0.5 mol%), 2 DCM, ↑↓ ee = 96–97% O n = 1, 70% O O O n = 2, 75% n AcN nH n = 3, 62% 4S-MACIM = CO2Me O N Doyle, M. P.; Dyatkin, A. B.; Roos, G. H. P.; Canas, F.; Pierson, D. A.; van Basten, A.; Mueller, P.; Polleux, P. J. Am. Chem. Soc. 1994, 116 , 4507–4508.

therefore Cu- and Rh-catalyzed cyclopropanation likely to be via metallacyclobutanes arrived from metal-bound carbene complex, analagous to the group 6 Fischer carbenes

40 Rh- and Cu-carbenes with α-diazocarbonyl compounds: an evolution in complexity

bicyclo[4.1.0]heptane skeleton H N2 copper bronze JACS Stork 1961, 83, 4678 c-hex, ↑↓, 11 h H O O (±)-sirenin skeleton H O

Cl 1) CH2N2 JACS Greico 1969, 91, 5660 2) copper bronze H c-hex, ↑↓, xx h O 55% over 2 steps

1) (COCl)2, PhH 2) CH2N2, Et2O JOC Welch 1974, 39, 2665 HO2C 3) copper powder THF, ↑↓, 2 h; r.t. 14 h Me 33% over 3 steps

41 Rh- and Cu-carbenes with α-diazocarbonyl compounds: not just addition to π-bond

C-H Insertion

O O copper bronze Tett Lett 1976 Nakata, 1515 c-hex, ↑↓, xx h H N2 H

C-C insertion

Me Me O O Me copper bronze JACS 1962 Danishefsky, 84, 879

c-hex, ↑↓, xx h Me Me N2 Me

42 Rh- and Cu-carbenes with α-diazocarbonyl compounds: examples

prostaglandins: diastereoselective (±)-8-epi-PGF2α O O CO Me 2 1 mol% Rh (octanoate) 2 4 CO2Me N2 TBDPSO DCM, r.t., 15 min 70% (+13% dia) TBDPSO H

Taber, D. F.; Herr, R. J.; Gleave, D. M. J. Org. Chem. 1997, 62, 194–198.

Regitz Diazo Transfer, RDT O O 1) K2CO3, n-Bu4NBr, O O O PhMe, 100 °C, 3 h; p-NBSA, DBU, N Ph 2 Ph 2) 40 °C, RBr, 18 h DCM, 0 °C, 1 h 83% 82% CO2Et CO2Et Taber, D. F.; Gleave, D. M.; Herr, R. J.; Moody, K.; Hennessy, M. J. J. Org. Chem. 1995, 60, 2283–2285.

KHMDS, THF, –78 °C, 40 min; O OHC n-pent CO2Me N2 LiBr, –78 °C, 2.5 h; then silylation TBDPSO 38% or 60% w/o ester (ester not compatible)

43 Rh- and Cu-carbenes with α-diazocarbonyl compounds: examples

Improved synthesis of diazo-carbonyl compounds:

LiHMDS, THF R1 O R1 O R1 O Danheiser, R. L.; Miller, R. F.; CF3CO2CH2CF3 MsN3, Et3N CF Brisbois, R. G.; Park, S. Z. R2 3 J. Org. Chem. 1990, 55, 1959–1964. 2 –78 °C, 10 mins H O, MeCN, 2 R 2 R N2 O 25 °C, 2.5 h R1 , R2 = alkyl, vinyl, aromatic, heteroaromatic; good to excellent yields

poly-fused polycycles

1) (COCl)2 Li, NH (l) 2) MeCHN2 O 3 O CO2H 3) CuSO4 81% 52% over 3 steps

Srikrishna, A.; Vijaykumar, D. J. Chem. Soc., Perkin Trans. 1 2000, 2583–2589.

44 Rh- and Cu-carbenes with α-diazocarbonyl compounds: examples

bicyclo[3.3.1]nonane skeleton O 2 mol% MeO OTIPS MeO OTIPS 1) MeI, t-BuOK OTIPS Cu(OTf)2•PhMe THF, –78 °C to r.t. MeO N O 2 2) 2 M HCl 4 mol% O OMe 58% OMe O O over 3 steps O N N PhMe, r.t. Me OTIPS O MeO OTIPS MeO O

H OMe OH Uwamori, M.; Nakada, M. Tetrahedron Lett. 2013, 54, 2022–2025. Uwamori, M.; Saito, A.; Nakada, M. J. Org. Chem. 2012, 77, 5098–5107.

45 Rh- and Cu-carbenes with α-diazocarbonyl compounds: examples

poly-fused polycycles

1) (COCl)2 Li, NH (l) 2) MeCHN2 O 3 O CO2H 3) CuSO4 81% 52% over 3 steps

Srikrishna, A.; Vijaykumar, D. J. Chem. Soc., Perkin Trans. 1 2000, 2583–2589.

enatioselective from simple achiral substrates

O H Rh [5(S)-MEPY] O 2 4 85% O ee = 92% O H N2 DCM

N O N O 5(S)-MEPY = Rh Rh MeO2C N O 4 N O O N Rh Rh

Hegedus, L. S.; Söderberg, B. C. G. Transion metals in the synthesis of complex organic molecules, 3rd Ed. (Sausalito, California: University Science Books, 2010), 216. See speciﬁcally references 143-145 for Chapter 6. 46 Rh- and Cu-carbenes with α-diazocarbonyl compounds: examples

catalyst effects regioselectivity for polyenes

1 mol% Rh2[5(R)-MEPY]4 DCM, ↑↓ 96% H H > 94% ee N2 O O O

O O "First macrocylization 1 mol% Rh (OAc) from intramolecular 2 4 O metal carbene" 63%

Rogers, D. H.; Yi, E. C.; Poulter, C. D. J. Org. Chem. 1995, 60, 941–945. Doyle, M. P.; Protopopova, M. N.; Poulter, C. D.; Rogers, D. H. J. Am. Chem. Soc. 1995, 117 , 7281–7282. For a review of ligand effects: Padwa, A.; Austin, D. J. Angew. Chem. Int. Ed. 1994, 33, 1797–1815.

47 Rh- and Cu-carbenes with α-diazocarbonyl compounds: examples

may even have cyclopropanation with aromatics O

CO2Me O 30 mol% Rh2(OAc)4 TBDPSO N 2 DCM, r.t., 4 h CHO CO2Me TBDPSO 50% O

O O TBDPSO CO2Me TBDPSO CO2Me O O

Hughes, C. C.; Kennedy-Smith, J. J.; Trauner, D. Org. Lett. 2003, 5, 4113–4115.

48 Rh- and Cu-carbenes with α-diazocarbonyl compounds: examples

MeO MeO CO Me 2 4 mol% Rh2(mandelate)4 CO Me H H 2 ODEIPS DCM, ↑↓, 10 mins; then DBU ODEIPS 65-84% depending on silyl group OMe OMe O N2 O OMe OMe

Ox. DBU addn Cope rearrange of divinylcyclopropane MeO MeO CO2Me CO Me MeO MeO H H 2 CO2Me H CO2Me R R H red. [3,3]- / [2+2] n R σ [Rh] elim 6-π electro R [Rh] O H O O O Frey, B.; Wells, A. P.; Rogers, D. H.; Mander, L. N. J. Am. Chem. Soc. 1998, 120, 1914–1915. An improved synthesis: Zhang, H.; Appels, D. C.; Hockless, D.; Mander, L. N. Tetrahedron Lett. 1998, 39, 6577–6580.

49 Au- and Pt-carbenes AcO P(t-Bu) O O 1 mol% Au(NTf2)L L = 2 Ph DCM 97%, no ee Ph

Buzas, A.; Gagosz, F. J. Am. Chem. Soc. 2006, 128, 12614–12615. "large alkynophilic proton"

O O O O O 5-exo-dig O can only revert or Ph Ph Ph protonolyze [Au] [Au] [Au] (but oxonium)

O H [Au] [Au] O O O O Ph 6-endo-tr/dig Ph OAc 6-endo-dig • O Ph Ph [Au] [Au]

AcO H AcO OAc H [Au] Ph Ph AcO [Au] Ph Ph [Au] 50 Au- and Pt-carbenes works with Ru too [Au] 2 mol% AuCl(PPh3), 2 mol% AgSbF6 Ts N DCM, 0 °C, 15 min Ts N Ts N H H 89%

Nieto-Oberhuber, C.; López, S.; Muñoz, M. P.; Jiménez Núñez, E.; Buñuel, E.; Cárdenas, D. J.; Echavarren, A. M. Chem. Eur. J. 2006, 12, 1694–1702.

AcO 2 mol% PtCl2 AcO H PhMe, 80 °C H 92% red. elimn Fürstner, A.; Hannen, P. Chem. Eur. J. 2006, 12, 3006–3019.

O O O carbonyl AcO first O O O H IV – Cl [2+2] Pt PtII PtIV H PtII 51 Non-carbene [2+1] reactions

52 Organocatalyzed [2+1] additions

OMe N 20 mol% OMe O O N H Cl O O 40 mol% NaI, Na2CO3 Bn MeCN, 80 °C, 24 h Bn 64%, 95% ee H

Et OMe N 20 mol% O O N H Cl O O 40 mol% NaBr, Na2CO3 Bn MeCN, 80 °C, 24 h Bn 48%, 94% ee H

Bremeyer, N.; Smith, S. C.; Ley, S. V.; Gaunt, M. J. Angew. Chem. Int. Ed. 2004, 43, 2681–2684.

53 Organocatalyzed [2+1] additions

54 Organocatalyzed [2+1]-cyclization

(100 mol%) OTMS

Me N Ar Ar H OHC OHC Ar = N NIS (1.0 eq) N Ts p-NBA (1.0 eq) Ts

i-Pr2O, 25 °C, 24 h 71% 91:9 er

(100 mol%) OTMS H N Ar Ar OHC OHC H

BnO2C CO2Bn NIS (1.0 eq) CO Bn p-NBA (1.0 eq) BnO2C 2 i-Pr O, 25 °C, 24 h 73% 2 93:7 er Luo, C.; Wang, Z.; Huang, Y. Nat. Commun. 2015, 6, 10041.

55 Formally an enantioselective [2+1]-cyclization but really a 1,5- then 1,3-cyclization

dynamic kinetic resolution possibly via

I OHC N OHC Ts N I Ts disfavoured

R R NH TsN N NIS 1 2 NTs R2R1N OHC or OHC N N I I Ts amination Ts first I

H OHC H TsN TsN TsN N N N N Ts I favoured

56 Conclusions

Cycolpropanes exist as targets themselves or intermediates with interesng reacvity.

Logical breakdown of cyclopropanaons into categories of synthons i. Make 1 C-C bond in cyclopropane i.e. 1,3-cylizaons i. Break 2 σ-bonds (Wurtz, eliminate HX, etc.) ii. Break 1 σ-bond and 1 π-bond (add to carbonyl, alkene, etc.) iii. Break 2 π-bonds (excite π-bond) ii. Make 2 C-C bonds in cycopropane i. Carbene addions to π-bonds ii. Carbene inserons in C-H or C-C bonds iii. 1,1-dicaon or 1,1-dianion and respecve partner

Carbene chemistry involoving α-diazocarbonyl compounds is a rich and fruiul ﬁeld.

57 Thanks for your attention!

58 Reserve Slides

59 O O O O O & X OR OR X Pyrethrin I X = Br, Cl

JOC, 1984, 49, 2682-2687 JOC, 1986, 51, 5429-5433

CCl3

Me N O O 2 BrCCl3 O N N CuBr2

[3,3] σ NMe2 O N Meerwein-Eschenmoser O Claisen rearrangment H2O2

OH O Me2N EtO OEt 1) H O/ H+ O OEt OEt 2 N OH

xylene, reflux O 2) SO2Cl O O 3) oxazolidinone [Claisen] 57%

Fe(CO)5 CCl4

NaH Cl O + CONR Cl3C N CONR2 2 Cl C O O Cl3C 3 75-87% cis: trans not work with Cu(I) 85:15 89% From cis-enolate

ENDO EXO Me Me Cl Cl H H Me Me Cl3C Cl3C H ONa NaO H NR2 NR2

Me Me H H Cl C Me Me 3 Cl3C H O H O

NR2 NR2

CIS TRANS Reserve slide: assumption for planar rings

63 Angles and Bonds

HCH = 114° HCH = 109.5 HCH = 117° ° CCC = 60° (by def.) CCH = 111.2 CCH = 121.5 ° ° CCH = 123° H H H H H H 1.51 H H 1.54 H 1.33 1.085 1.084 1.09 H H H H H H H

64 Conformation: ring strain

Cyclopropane

Cyclobutane

65 Angular Strain and Gauche/ Eclipsing Strain Pﬁtzer and … strain

66 67 How do you explain the following observation?

“Ring strain confers exceponal reacvity to the cyclopropane ring.” De Simone, F; Waser, J. Chimia, 2009, 63, 162-167.

OR E E ROH E R R R no ring strain Markovnikov

E E depending on ring strain: substitution 27.5 kcal mol−1 R R pattern

E ring strain: no reaction 26.5 kcal mol−1 R

c.f. C–C bond dissociation energy is ∼83-85 kcal mol−1

Ring strain might provide a strong thermodynamic driving force for reacon but is doesn’t explain the reacvity. A suitable answer must therefore invoke bonding.

68 Problem: tightest angle between any AOs is 90° (e.g. orthogonal p-orbitals) but in cyclopropane we have to accomodate a bond angle of 60°

Pauling τ-bond treatment Hückel σ/π-bond treatment

Ψ(E',a) Ψ(E',b)

Ψ(A2')

Ψ(E',c) Ψ(E',d)

Ψ(A1') 22° and ~20% less effective overlap

"the overall distribuon of electrons [...] is exactly the same" [in the two models]. – Ian Fleming At least theorecally and mathemacally, and assuming that the basis sets are valid (interconverble). An excellent resource for Walsh’s theory using methylene as basis set: http://www.bluffton.edu/~bergerd/chem/walsh/derive.html, and references therein for the full story. 69 Applying Bent’s rule The H−C−H angle in cyclopropane is measured as 114 degrees. From this, and using Coulson's Theorem 1+ λ 2 cos(114) = 0 where λ represents the amount of p-character in the AOs directed along the C−H bond in cyclopropane and can be deduced to be sp2.46 hybridized. Now, using the equaon 2 2 + =1 1+ λC−H 1+ λC−C (which says that summing the s-character over all AOs at a given carbon must be total to 1) 3.74 we ﬁnd that λc−c = 3.74 so that the re-hybridized AOs directed along the C−C bond are sp hybridized. We see that the C−C bonds in cyclopropane are very high in p-character (c.f. below for ethene). It is this high p-character that allows cyclopropane to behave in a similar fashion to an alkene in terms of stabilizing an adjacent charge or undergoing electrophilic substuon with bromine. Also tells us C−C−C interorbital angle of 105.5 degrees.

A similar treatment for ethene gives sp2.20 for the AOs along the C−H bonds and sp4.33 for along the C−C bonds (i.e. Pauling’s 2 x τ-bonds as a point of comparison for cyclopropane). ((Or a single p-orbital and an sp1.7 C−C direconalized “σ-bond” as in Hückel’s treatment)). http://chemistry.stackexchange.com/questions/10653/why-does-cyclopropane-give-bromine-water-test/ 10666#10666 And, https://en.wikipedia.org/wiki/Bent%27s_rule 70 Applying Bent’s rule

Coulson's theory and Bent's rule Hybridization of C AOs Hybridization of C AOs interorbital HCH angle along C–H bond axis associated with C–C bond angle

114° 2.46 3.74 105.5° (measured) sp sp (deduced)

approximated 2 5 102° as 120° sp sp (deduced)

N.B.: for sp3.74-hybridized C atom AOs associated with the C–C bonds we have assumed that the C atom AOs associated with 23° and the C–H bonds are fixed/ directionalized exactly along this axis. interorbital angle is 105.5° sp2 (C–C) and sp5 (C–H) AOs have also been used with incorrect approximations, at least as incorrect as using sp2-hybridized AOs in ethene, but this model does contain some physical significance as it qualitatively explains cyclopropane deformation density.

71 Bonding by use of number crunching

Ψ(E',a) Ψ(E',b)

Ψ(A2')

Ψ(E',c) Ψ(E',d)

Ψ(A1')

Walsh orbitals: sp2-hybridized C AOs C-H σ 6 H atoms and 4 C atoms gives 18 valence AOs, and 18 MOs. All occupied (18 electrons) MOs and LUMO are depicted below. Calculaon from valence orbitals, BP86/cc-PVTZ, D3h. 72 Bonding by use of number crunching

C-H σ* Ψ(E',a) Ψ(E',b)

Ψ(A2')

Ψ(E',c) Ψ(E',d)

Ψ(A1')

C-H σ Walsh orbitals: sp2-hybridized C AOs

C-H σ 6 H atoms and 4 C atoms gives 18 valence AOs, and 18 MOs. All occupied (18 electrons) MOs and LUMO are depicted below. Calculaon from valence orbitals, BP86/cc-PVTZ, D3h. 73 Banana Bond

X-ray diffraction of cis-1,2,3-tricyanocyclopropane: Hartman, A.; Hirshfeld, F. L. Acta Crystallographica 1966, 20 (1), 80–82.

74 σ-aromaticity???

6 σ-electrons 4n + 2 aromatic Dewar 1984 (n=1)

4n + 2 Cremer, 2 "surface" aromatic Gauss 1986 electrons (n=0) Ψ(A1') 3-centre, 2-electron bond

H H H H B H H H H

Dewar, M. J. S. J. Am. Chem. Soc. 1984, 106, 669–682; Cremer, D.; Gauss, J. J. Am. Chem. Soc. 1986, 108, 7467–7477. For recent discrepancies of this theory: Carion, R.; Champagne, B.; Monaco, G.; Zanasi, R.; Pelloni, S.; Lazzere, P. J. Chem. Theory Comput. 2010, 6, 2002–2018; Pelloni, S.; Lazzere, P.; Zanasi, R. J. Phys. Chem. A 2007, 111, 8163–8169. Reviewed in: Wu, W.; Ma, B.; I-Chia Wu, J.; Schleyer, P. V. R.; Mo, Y. Chem. Eur. J. 2009, 15, 9730–9736. 75 σ-aromaticity???

6 σ-electrons 4n + 2 aromatic Dewar 1984 (n=1)

4n + 2 Cremer, 2 "surface" aromatic Gauss 1986 electrons (n=0) Ψ(A1') 3-centre, 2-electron bond aromatic H H H H H (+) (+) H E E H H H E H H H HOMO

aromatic HH HH E E

HH HH

k ROH OSO Ar OR 2 k' TsO AcO AcOH ROH OSO2Ar OR 11 4000k' 10 k (!!!) OMe OMe retention (trans)

LUMO: empty C-O σ* orbital O 0 electrons Ts 4n + 2 electrons HOMO: filled π orbital 2 electrons

via aromatic TS

or... α-cation to aromatic cyclpropane

delocalized aromatic cyclopropenyl-like cation (3-centre, 2-electron)

77 Reviews • Discussions of bonding, reacvity, and reacons of cyclopropanes: Wong, H. N. C.; Hon, M. Y.; Tse, C. W.; Yip, Y. C.; Tanko, J.; Hudlicky, T. Chem. Rev. 1989, 89 (1), 165–198; (b) Walsh, A. D. Trans. Faraday Soc. 1949, 45, 179–190; (c) de Meijere, A. Angew. Chem. Int. Ed. Engl. 1979, 18 (11), 809–826; (d) Cavi, M. A.; Phun, L. H.; France, S. Chem. Soc. Rev. 2014, 43 (3), 804–818.

• Cyclopropanaons: (a) caon (bio-inspired): Taylor, R. E.; Engelhardt, F. C.; Schmi, M. J. Tetrahedron 2003, 59, 5623–5634; (b) from terminal epoxides: M Hodgson, D.; Salik, S. Curr. Org. Chem. 2015, 20 (1), 4–18; (c) stereoselecve: Lebel, H.; Marcoux, J.-F.; Molinaro, C.; Charee, A. B. Chem. Rev. 2003, 103 (4), 977–1050; (d) asymmetric ylide: Li, A.-H.; Dai, L.-X.; Aggarwal, V. K. Chem. Rev. 1997, 97 (6), 2341–2372.

• Biosynthesis and metabolism: (a) Wessjohann, L. A.; Brandt, W.; Thiemann, T. Chem. Rev. 2003, 103 (4), 1625–1648; (b) Thibodeaux, C. J.; Chang, W.-C.; Liu, H.-W. Chem. Rev. 2012, 112 (3), 1681–1709.

• Books

• Misc: Gong’s topic review (database: tr2014_02); Myers’ Chem 115; various group meengs on other group’s websites; chemistry stack exchange

78 Original desired structure I. Physical consideraons of cyclopropanes

II. Reacvity and basicity of cyclopropanes

III. Biosynthesis of cyclopropanes and metabolism ii. Enzyme approach iii. Rearrangement approach

IV. Prevalence of cyclopropanes i. In natural products and in drug discovery ii. In ring opening during total synthesis

V. Intramolecular cyclopropanaons with applicaons i. 1,3-eliminaon-like ii. 1,3-coupling-like iii. Carbene or carbenoid addions to π-bonds