Helicenes:Synthesis and Applications

KEVIN A. ROBB

SED GROUP MEETING – MAY 20, 2014

OutlineBackground

Synthesis◦ Early methods

◦ Photochemical strategy

◦ Diels-Alder strategy

Application◦ Chiral ligands in asymmetric catalysis

◦ Helicenes as organocatalysts

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HelicenesClass of polyaromatic molecules

◦ Characterized by several (4 or more) ortho-fused benzene (or hetero-aromatic) rings

◦ Adopt a helical structure

◦ Very large specific rotation◦ ± 1670° (for [5]helicene) up to ± 9620° (for [13]helicene)

◦ [α]Tλ =

αTλ

𝑙 ·𝑐

◦ “Continuously chiral”

M. Gingras. Chem. Soc. Rev. 2013, 42(3), 968-10063

[7]thiaheterohelicene

[6]helicene

NomenclatureUse [n]helicene for unsubstituted systems

◦ n = number of ortho-fused rings

◦ Also common to use prefixes

Directionality◦ Right-handed helicenes are denoted P (plus) or Δ

◦ Left-handed helicenes are denoted M (minus) or Λ

(P)-[7]helicene or (P)-heptahelicene

(M)-[6]helicene or (M)-hexahelicene

M. Narcis and N. Takenaka. Eur. J. Org. Chem. 2014, 21-344

Some terminology…Axial Chirality:

◦ No stereogenic centers

◦ Molecule contains an axis (single bond) whose substituents are held in a particular arrangement due to steric bulk

Helicity:◦ Defined by a 3-dimensional space curve

Axial Chirality: (S)-BINOL Helicity: (P)-hexahelicene(S)-VAPOL: Both?

M. Narcis and N. Takenaka. Eur. J. Org. Chem. 2014, 21-345

OutlineBackground

Synthesis◦ Early methods

◦ Photochemical strategy

◦ Diels-Alder strategy

Application◦ Chiral ligands in asymmetric catalysis

◦ Helicenes as organocatalysts

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Hexahelicene - SynthesisFirst synthesis (Newman and Lednicer, 1956)

M. S. Newman and D. Lednicer. J. Am. Chem. Soc. 1956, 78(18), 4765-47707

Hexahelicene - ResolutionResolution with TAPA

◦ 2-(2,4,5,7-tetranitro-9-fluorenylideneaminooxy)-propionic acid

◦ Novel technique at the time for resolution of a neutral molecule

◦ Formation of a diastereomeric charge-transfer complex

Specific rotations:◦ (–)-helicene: [α]24

D = -3640°

◦ (+)-helicene: [α]25D = +3707°

(P)-[6]helicene(M)-[6]helicene

M. S. Newman and D. Lednicer. J. Am. Chem. Soc. 1956, 78(18), 4765-47708

(S)-(–)-TAPA

H-NMR

9 M. S. Newman and D. Lednicer. J. Am. Chem. Soc. 1956, 78(18), 4765-4770

OutlineBackground

Synthesis◦ Early methods

◦ Photochemical strategy

◦ Diels-Alder strategy

Application◦ Chiral ligands in asymmetric catalysis

◦ Helicenes as organocatalysts

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Photochemical ApproachOxidative photocyclization of stilbene-like molecules

◦ The intermediate trans-dihydrophenanthrene is trapped with I2 or O2

◦ Only the cis-isomer is reactive, but the trans-isomer can still be used since cis-trans isomerization of stilbene derivatives occurs readily under the conditions

Cis-stilbene Phenanthrene

F. B. Mallory and C. W. Mallory. Organic Reactions. 1984, 3011

MechanismCyclization:

Oxidative Trapping:

◦ I2 is typically used rather than oxygen, since hydrogen abstraction by iodide is more exothermic

F. B. Mallory and C. W. Mallory. Organic Reactions. 1984, 3012

Competing ReactionsProblem: [2+2] cycloadditions

Solution: Run reaction at low concentrations (0.001 M or less)

Stilbene dimerization Phenanthrene-Stilbene Cycloaddition

F. B. Mallory and C. W. Mallory. Organic Reactions. 1984, 3013

Hexahelicene (revisited)R. H. Martin, 1968

◦ Cyclization precursor accessed through Wittig chemistry

14 Martin et al. Tetrahedron Lett. 1968, 9(31), 3507-3510

80% yield

Larger…Heptahelicene (R. H. Martin, 1967)

◦ Stilbene-like precursor accessed by dehydration reaction

Martin et al. Tetrahedron Lett. 1967, 8, 743-74415

Racemic synthesis – resolution was achieved by hand-picking crystals!!

66% yield

… and larger[11]Helicene (R. H. Martin, 1975)

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• Wittig reaction proceeds in 97% yield• Photocyclization proceeds in 84% yield• Up to [14]helicenes prepared in this manner

R. H. Martin and M. Baes. Tetrahedron 1975, 31(17), 2135-2137

Substituted Helicenes[6]-Heliphos (Reetz, 1997)

◦ Cyclization precursor accessed with Wittig chemistry

◦ Photocyclodehydrogenationproceeds in 10-50 % yield

Reetz et al. Tetrahedron Lett. 1997, 38(18), 3211-321417

Substituted Helicenes[5] and [7] Helicenes (Marinetti, 2004)

◦ Precursor accessed via Heck reaction

◦ Propylene oxide traps HI as it forms

Marinetti et al. Eur. J. Org. Chem. 2004, 1517-152218

[Pd] = Herrmann’spalladacycle

R = H, Me, OMe,OH, CN

RegioselectivityControlling regioselectivity

◦ How can unwanted constitutional isomers be discriminated against?

◦ Often, π-stacking interactions help organize the transition state

◦ Another option is to use a “bromine auxiliary”

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75 % yield for cyclization step (as opposed to 20 % when bromine auxiliary is not used)

A. Sudhakar and T. J. Katz. Tetrahedron Lett. 1986, 27(20), 2231-2234

Heterohelicenes[7]Thiaheterohelicenes (Tanaka, 1998)

◦ Photochemical approach is easily applied

20 Tanaka et al. J. Chem. Soc., Perkin Trans. 1. 1998, 5, 935-940

Asymmetric PhotocyclizationAsymmetric synthesis with circularly polarized light (first example)

◦ Enantiomeric excess < 0.20% (determined by optical rotation), but still outside the margin of experimental error

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(M)-helicene: [α]23°D = -7.5 ± 0.3°

(P)-helicene: [α]23°D = +7.9 ± 0.6°

Kagan et al. J. Am. Chem. Soc. 1971, 93, 2353-2354

OutlineBackground

Synthesis◦ Early methods

◦ Photochemical strategy

◦ Diels-Alder strategy

Application◦ Chiral ligands in asymmetric catalysis

◦ Hetero-helicenes as organocatalysts

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Diels-Alder Approach2 General Classes

◦ Addition of dienophile to 3,3’,4,4’-tetrahydro-1,1’-binapthalenes

◦ Addition of dienophile to vinylbenzenes

M. Gingras. Chem. Soc. Rev. 2013, 42(3), 968-100623

Early Work[5]-Helicene (Weidlich, 1938)

◦ First example of using the Diels-Alder approach

◦ Tetrahydrobinaphthalene used as diene

◦ Cycloaddition step proceeds in 75 % yield

H. A. Weidlich. Ber. 1998, 71, 1203-120924

Addition to vinylbenzenes[5]-Helicenebisquinone (Katz, 1990)

◦ Cycloaddition proceeds in 17 % yield

◦ Immediate Diels-Alder product is oxidized by excess benzoquinone

◦ How to increase yield?

Katz et al. Tetrahedron Lett. 1990, 31(28), 3983-398625

Diels-Alder: Increasing the YieldSubstituted [5] and [6]-Helicenebisquinones (Katz, 1997)

◦ Yields can be increased by increasing electron density on the diene

17 %, R = H (previous slide)50 %, R = OC12H25

6 %, R1 = H, R2 = H13%, R1 = H, R2 = OMe47%, R1 = OMe, R2 = H42%, R1 = OTBDMS, R2 = H

Katz et al. J. Am. Chem. Soc. 1997, 119, 10054-1006326

Asymmetric Diels-AlderAsymmetric synthesis with chiral sulfinylquinones

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(M)-helicenebisquinone80 % ee, 22 % yield

Carreño et al. J. Org. Chem. 1999, 64, 1387-1390

OutlineBackground

Synthesis◦ Early methods

◦ Photochemical strategy

◦ Diels-Alder strategy

Application◦ Chiral ligands in asymmetric catalysis

◦ Hetero-helicenes as organocatalysts

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Asymmetric catalysisWhy use helicenes in asymmetric catalysis?

◦ Rigidity/thermal stability

◦ Define a large chiral pocket (“continuously chiral”)

◦ Highly amenable to charge-transfer complexation(polarizable)

M. Gingras. Chem. Soc. Rev. 2013, 42(3), 1051-109529

Early ApplicationsEpoxidation (Martin, 1986)

◦ Stoichiometric additive

◦ First application of a helicene in an enantioselective reaction

(P)-(+)-2-cyano-[7]helicene

92% yield, 99.8% ee

(M)-(-)-2-cyano-[7]helicene

84% yield, 97.6% ee

Martin et al. Bull. Soc. Chim. Belg. 1986, 95, 547-553 and 557-56630

Early ApplicationsHydrogenation (Reetz, 1997)

◦ First example of catalytic use of a helicene in asymmetric synthesis

(P)-PHelix:

54% yield, 39% ee

Reetz et al. Tetrahedron Lett. 1997, 38(18), 3211-321431

Helical PhosphinesKinetic Resolution with PHelix (Reetz, 2000)

Reetz et al. J. Organomet. Chem. 2000, 603, 105-10932

Helical PhosphinesKinetic Resolution with PHelix (Reetz, 2000)

◦ Although PHelix is formally a diphosphine, it is more likely behaving as a monodentate ligand

◦ Multiple signals in 31P NMR◦ η3-C3H5PdCl-PHelix complex

◦ Main peak at 33.6 ppm

◦ Smaller signals at 24.1, 27.2, 27.9, and 28.0 ppm

◦ Crystal structure◦ P1–P2 distance in PHelix is too large to chelate metal

Reetz et al. J. Organomet. Chem. 2000, 603, 105-10933

6.481(1) Å [P1–P2]

Unfunctionalized HelicenesSoai (2001)

◦ First example of a hydrocarbon as an asymmetric catalyst◦ “Chiral inducer” to an asymmetric autocatalytic process

◦ Origin of enantioselectivity arises from formation of a charge-transfer complex between the aldehyde and helicene

◦ Evidence of a charge-transfer complex can be observed in proton NMR◦ Upfield shift of aldehyde and pyrimidine ring proton signals

◦ Shift shows a linear correlation with amount of helicene added (up to 6.3 equiv)

95% yield, 95% ee

Soai et al. Angew. Chem., Int. Ed. 2001, 40(6), 1096-109834

Proton signal Δδ (per equiv. of helicene)

A -13.3 Hz

B -9.1 Hz

C -1.1 Hz

Helicenes in OrganocatalysisModular synthesis of 1-azahelicenes (Takenaka, 2008)

◦ Cyclization is achieved through an intramolecular Stille coupling

◦ Variation of Wittig partner allows access to a number of azahelicenes

Takenaka et al. Angew. Chem., Int. Ed. 2008, 47(50), 9708-971035

Helicenes in OrganocatalysisDesymmetrization of meso epoxides with chlorosilane

◦ Degree of stereoselectivity is highly substrate-dependent

R % yield % ee

R = Ph 77 % 94 %

R = 2-naphthyl 76 % 92 %

R = BnOCH2 72 % 65 %

R = alkyl 74 % 33 %

Takenaka et al. Angew. Chem., Int. Ed. 2008, 47(50), 9708-971036

Substrate scope:

Lewis Base CatalysisActivation of allenyltrichlorosilane (Takenaka, 2011)

◦ Synthesis and application of a bidentate Lewis basic helicene

18 examples, 55-98% yield, 59-96% ee

Takenaka et al. Org. Lett. 2011, 13(7), 1654-165737

Lewis Base CatalysisActivation of allenyltrichlorosilane (Takenaka, 2011)

◦ Proposed model of stereochemical controlSignificant drop in ee when this catalyst was used instead (33% ee)

Significant drop in ee (59% ee)when this substrate was used(R = aryl for all other substrates)

Takenaka et al. Org. Lett. 2011, 13(7), 1654-165738

H-Bond Donor CatalysisHelicene-based 2-aminopyridinium ions (Takenaka, 2010)

◦ Application: addition of dihydroindoles to nitroalkenes

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Catalyst synthesis:

• 19 examples• 10-90% yield• 60:40 to 98:2 er

Takenaka et al. J. Am. Chem. Soc. 2010, 132(13), 4536-4537

H-Bond Donor CatalysisHelicene-based 2-aminopyridinium ions (Takenaka, 2010)

◦ Stereochemical model:

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Enantioselectivity drops off rapidly for this catalyst (adamantyl group removed):

Takenaka et al. J. Am. Chem. Soc. 2010, 132(13), 4536-4537

Concluding RemarksPowerful synthetic methods exist to construct helicenes

◦ Photocyclization strategy and Diels-Alder strategy are most common

◦ Can generate both functionalized and unfunctionalized helicenes

Helicenes have displayed varied roles in a number of catalytic processes◦ Chiral ligands for transition metals

◦ Organocatalysis

◦ Lewis basic helicenes

Still a young field!◦ Reports of catalytic uses of helicenes date back only to the 1990s

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ReferencesReviews:

◦ M. Narcis and N. Takenaka. Eur. J. Org. Chem. 2014, 21-34

◦ M. Gingras et al. Chem. Soc. Rev. 2013, 42, 968-1006 (Part 1), 1007-1050 (Part 2), 1051-1095 (Part 3)

All other sources are cited on the slides on which they appear.

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